Session Details, Speaker Biographies & Abstracts

Jason Bartz, PhD, Chair and Professor, Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE, U.S.A.

Biography: Jason C. Bartz, PhD is Professor and Chair in the Department of Medical Microbiology and Immunology at the Creighton University School of Medicine. Dr. Bartz earned a Ph.D. at the University of Wisconsin, Madison. Dr. Bartz investigates interspecies transmission, pathogenesis, and the biology of prion strains whose work has sought to understand how a protein-only infectious agent can perform complex biological tasks.

Abstract: Transport of prion strains in the peripheral and central nervous system
Extraneural prion inoculation generally establishes infection in lymphoreticular system tissues prior to neuroinvasion of the peripheral nervous system (PNS). Once prions enter the PNS, prions spread to the central nervous system where they lead to neurodegeneration and eventual death of the host. To investigate the pathways and rates of prion transport in the nervous system, the temporal and spatial spread of PrPSc was determined following inoculation of the sciatic nerve. We found that PrPSc was first detected in ventral motor neurons (VMNs) of the lumbar spinal cord ipsilateral to the side of sciatic nerve inoculation. From VMNs, prions were specifically transported by four descending motor tracks to synaptically connected structures in the brainstem and brain. This pattern of prion spread was found to be independent of the prion strain suggesting this is a common property of prions. More recent work directly measuring PrPSc velocities in the sciatic nerve of live animals indicates that PrPSc is transported at i) a rate consistent with fast axonal transport, ii) does not require PrPC for transport and iii) similar velocity profiles are observed between prion strains. As this system targets prion strains to the same population of VMNs it has allowed for a detailed investigation of prion strain interference and evolution. We have found that prion strain interference is dependent on the relative onset of conversion of the strains in a common population of cells that compete for PrPC. These parameters dictate which prion strain will emerge from a mixture. Finally, others have found that injection of prion-like proteins into the sciatic nerve results in the spatial and temporal development of neuropathology that is consistent with spread along anatomically connected neuroanatomical pathways. Overall, this system may lead to a better understanding of axonal transport of prion and prion-like proteins.

Joaquín Castilla, PhD, IKERBasque Research Professor, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Derio, Spain

Biography: Professor Dr. Joaquín Castilla is a senior investigator currently working at CIC bioGUNE, with over 25 years of experience in prion research. He has worked at several prestigious research institutions, including the Serono Research Institute in Switzerland, the University of Texas Medical Branch, and Scripps-Florida, where he led an independent research group. Dr. Castilla's research focuses on prion propagation both in vitro and in vivo, exploring strain and species barriers. His notable achievements include developing sensitive prion detection methods, generating prion infectivity in vitro, detecting prions in blood, and creating diverse recombinant prions, which have provided invaluable insights into the fundamental aspects of the prion field. He has extensive experience collaborating on international projects, has supervised 20 doctoral theses, and has published over 120 peer-reviewed articles in top journals, significantly contributing to our understanding of the molecular mechanisms underlying prion propagation.

Abstract: Insights from multi-species bona fide prion generation: Perspectives for prion-like disorders
Our study introduces a novel methodology for generating infectious prions de novo, enabling a comprehensive analysis of protein misfolding across more than 400 recombinant prion proteins from various mammalian species. Using the Protein Misfolding Shaking Amplification (PMSA) technique, we classified these proteins based on their spontaneous misfolding propensity and conformational variability, providing a systematic evaluation of misfolding processes. We successfully produced infectious prions from over 250 species, including bats, deer, sheep, cows, mink, pigs, humans, dogs, rabbits, and rodents, confirming the infectivity of many through detailed inoculation experiments. This research allows us to rank the misfolding propensities of wild-type prion proteins and establish valuable correlations between protein structure and misfolding potential, offering insights into key factors involved in prion transmission and interspecies barriers. This strategy, designed to decipher the guidelines for spontaneous misfolding in classical prions, could also be applied to prion-like proteins. During the talk, we will discuss the implications of conformers and strains in both prion and prion-like diseases, and how this approach—using different species to better understand misfolding—can be extended to prion-like proteins. The use of diverse species enhances our understanding of misfolding mechanisms and strain variability, both of which are crucial for prion and prion-like pathologies. Additionally, this study lays the groundwork for innovative therapeutic strategies, particularly those based on dominant-negative principles aimed at inhibiting or reversing disease progression by blocking endogenous prion propagation. These approaches hold promise not only for prion diseases but also for prion-like disorders. Our methodology thus offers a valuable framework for understanding prion biology, with broader implications for neurodegenerative diseases and potential applications in future diagnostics and therapeutics. 

Glenn Telling, PhD, Director, Prion Research Center, Colorado State University, Fort Collins, CO, U.S.A. (Moderator)

Biography: Telling Laboratory is one of only a handful of groups with the resources and expertise in whole animal, transgenic, cell biological, biochemical, molecular genetic, and in vitro approaches to studying prion disease, and they are widely considered to be among the leaders in the field. Dr. Telling has been recognized for his studies on human prions, the molecular basis of the species barrier, prion strains and their zoonotic potential, and chronic wasting disease (CWD) of cervids. Following baccalaureate and Masters’ training at Oxford University and Doctoral training at Carnegie Mellon University respectively, his involvement in prion disease research began in the early 1990’s as a postdoctoral trainee with Nobel Laureate Stanley Prusiner. Dr. Telling subsequently developed a well-funded and internationally acclaimed independent career. He was recruited to Imperial College, London by the Medical Research Council (MRC) at the height of the BSE/CJD crisis, to establish a research group in the newly created MRC Prion Unit. Following a subsequent successful tenure at the Sanders Brown Center on Aging at the University of Kentucky Medical Center, he was recruited to establish and direct the Prion Research Center (PRC) at Colorado State University in July 2011. In establishing the PRC, they recruited members with diverse expertise including protein chemistry, molecular biology, immunology, infectious diseases, mammalian and yeast cell biology, genetics, mouse transgenesis, neurodegeneration, epidemiology, and public and animal health. The PRC is well placed to study CWD because of its local origin and regional importance. The publication output of his lab has been consistent, and has exerted a powerful and sustained influence on the field. As an independent investigator, he has received uninterrupted funding from the National Institutes of Health since 2000. Additional research funding has been secured through the Departments of Defense and Agriculture, as well as other UK and Canadian funding agencies. He has published over 100 peer-reviewed research articles in leading research journals including Science, PNAS and Cell, as well as 13 book chapters and over 140 conference abstracts. His expertise provides him the opportunity to serve the broader scientific community in numerous settings. His ability to liaise and collaborate with the prion community is also significant. In combination with skills and perspectives provided by Telling Laboratory's talented collaborators, Telling Laboratory is in a unique position to investigate the molecular events underlying prion propagation, species barriers and strains, which remain the overarching goals of Dr. Telling's research program.

Mathias Jucker, PhD, German Centre for Neurodegenerative Diseases (DZNE) and University of Tübingen, Germany

Biography: Mathias Jucker, Ph.D., is Professor of Cell Biology of Neurological Diseases at the Hertie Institute for Clinical Brain Research at the University of Tübingen and the German Center for Neurodegenerative Diseases (DZNE). He obtained his Ph.D. at the Swiss Federal Institute of Technology in Zürich. He then worked as postdoc and research scientist at the National Institute on Aging in Baltimore, USA. He returned to Switzerland as an assistant professor and was appointed to his current position in Tübingen, Germany, in 2003. His main areas of research are the cellular and molecular mechanisms responsible for brain aging and Alzheimer’s disease. He has made important discoveries on the basic mechanisms underlying neurodegenerative diseases, such as the role of self-propagating pathogenic protein aggregates in Alzheimer’s disease and other disorders of the aging brain. Noteworthy are his efforts to translate fundamental and preclinical research into clinical studies and his commitment to the Dominantly Inherited Alzheimer Network (DIAN). Along with his scientific achievements Mathias Jucker has successfully promoted young scientists. He is the spokesman of the Graduate School of Cellular and Molecular Neuroscience in Tübingen, Germany, and has supervised more than thirty doctoral students, many of whom have since become group leaders and professors at renowned research institutions.

Abstract: Targeting Aβ seedsThe commonality of many neurodegenerative disorders is the progressive temporal and spatial aggregation of specific proteins in the brain. The most prominent proteopathy is Alzheimer’s disease (AD), in which the aggregation and seeded propagation of amyloid-β peptide (Aβ) triggers AD pathogenesis, including neuronal Tau inclusions and neurodegeneration. Current therapeutic strategies focus on early disease stages and aim to inactivate Aβ seed propagation before the onset of neurodegeneration. However, to develop such primary prevention approaches, a mechanistic understanding of early disease biomarkers is essential, as they are a prerequisite for monitoring therapeutic efficacy in a clinical setting.

Kelvin C. Luk, PhD MTR, Research Associate Professor of Pathology and Laboratory Medicine, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Biography: Dr. Luk is Research Associate Professor of Pathology and Laboratory Medicine at the University of Pennsylvania’s Center for Neurodegenerative Disease Research. He received his BSc in Microbiology and Immunology and PhD in Pathology from McGill University. He completed his postdoctoral training at the University of Pennsylvania where he also obtained a Masters in Translational Research. Dr. Luk’s research aims to untangle the relationship between the formation of alpha-synuclein pathology that characterizes Parkinson’s disease (PD) and related disorders with its role in neuronal dysfunction and degeneration. Using a multidisciplinary approach spanning in vitro, cell-based, and in vivo models, his team interrogates the mechanisms by which misfolded forms of this protein act as pathological agents that self-propagate and spread throughout the CNS. His group also focuses on developing new cell- and animal-based models of synucleinopathy and innovative tools for the detecting disease-related proteins. This knowledge is further leveraged towards novel therapeutic strategies for neurodegenerative disorders that target these processes.

Abstract: Reconstructing the disease trajectories of alpha-synucleinopathies through in vivo seeding models
Alpha-synuclein represents a major protein component of Lewy pathology found in Parkinson’s disease and related neurodegenerative disorders. Mounting evidence indicates that misfolded alpha-synuclein is capable of self-replication and transmission within neuronal networks with prion-like properties. The mechanisms that govern these processes are still being elucidated, as are the downstream consequences that contribute to neurodegeneration. This presentation will review recent clinical findings and data from experimental models that leverage this seeding phenomenon to understand local and global processes that influence synucleinopathy progression, and how they might contribute to the disease trajectories observed in subjects with Lewy body diseases.

Sue-Ann Mok, PhD, Assistant Professor, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada

Biography: Dr. Mok obtained her PhD in Cell Biology from the University of Alberta before completing postdoctoral studies at the University of California, San Francisco. Dr. Mok returned to the University of Alberta to start her independent research program in the Dept. of Biochemistry and is currently an Associate Professor. Her research is aimed at dissecting the complex relationships linking protein sequence, amyloid structure and function/dysfunction using biochemical and cell biology approaches.

Abstract: Diversifying the tau amyloid toolkit to probe structure-function relationships
Multiple tau amyloid polymorphs have been identified in tauopathies. Current evidence links individual polymorphs with specific tauopathies which suggests that underlying conditions/events lead to their initial formation and dominant propagation in disease. An improved understanding of how and why specific tau amyloid polymorphs effectively promote dysfunction at a cell and organism level would lend insight into how they can be effectively targeted. Our lab has developed high-throughput biochemical platforms to rapidly probe for changes in de novo formed tau aggregate structures in response to manipulations such as mutations and cofactors. Using our techniques, we have identified single disease-associated missense mutations that encode for over a dozen alternate tau aggregate conformations. With our new amyloid toolkit, we are now poised to define the specific elements of tau amyloid structure responsible for its prion properties. 

Joel Watts, PhD, Associate Professor, Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada (Moderator)

Biography: Dr. Watts obtained his PhD in Laboratory Medicine and Pathobiology from the University of Toronto and then conducted postdoctoral research in the lab of Stanley Prusiner at the University of California San Francisco. He is currently a Principal Investigator at the Tanz Centre for Research in Neurodegenerative Diseases, an Associate Professor within the Department of Biochemistry at the University of Toronto, and is the Canada Research Chair in Protein Misfolding Disorders. His research interests include studying the role of protein aggregate strains in Alzheimer’s disease and Parkinson’s disease as well as exploiting the unique properties of the bank vole prion protein to understand how prions form spontaneously in the brain.

Stanley B. Prusiner, MD, Director, Institute for Neurodegenerative Diseases, University of California, San Francisco Weill Institute for Neurosciences, San Francisco, CA

Virtual

Byron Caughey, PhD, Rocky Mountain Labs, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT (Moderator)

Biography: Dr. Caughey received his Ph.D. in biochemistry from the University of Wisconsin-Madison in 1985 and completed postdoctoral studies in pharmacology at Duke University Medical Center from 1985 to 1986. He has conducted TSE/prion research in the Laboratory of Persistent Viral Diseases since 1986. He became a tenured senior investigator in 1994. Dr. Caughey is also an editor for the Journal of Virology and a Fellow of the American Academy of Microbiology.

Abstract: Structural biology of PrP prions
Multiple proteins can assemble into abnormal, self-propagating, and sometimes transmissible, fibrils that can cause neurodegenerative diseases. The most overtly infectious of these are PrP-based prion diseases, with chronic wasting disease (CWD) of cervids apparently being the most efficiently transmitted by natural routes. Recent cryo-EM studies have revealed the structures of tissue-derived amyloid fibrils of several experimentally rodent-adapted prion strains and humans with F198S Gerstmann-Straussler-Scheinker syndrome (GSS). The mutant GSS fibrils have much smaller protease-resistant cores than the rodent prions and are much less infectious for hosts other than bank voles. Comparisons of cryo-EM structures of various PrP fibrils have begun to reveal structural underpinnings of prion transmissibilities, species barriers, and strain diversity.
We have now solved the structure of the prion fibrils isolated from a CWD-infected deer at 2.8 Å resolution (Alam et al., Acta Neuropathologica 2024). This structure is the first of a natural prion from mammalian host expressing wildtype PrP. Although these CWD fibrils share some general features with the rodent-adapted prion structures, they differ markedly in many other features, including a ~180° twist in the relative orientation of the N- and C-terminal lobes. This structure has suggested mechanisms for the deer-to-human transmission barrier and should facilitate rational approaches to CWD prevention and therapeutics.
We have also performed molecular dynamics simulations that test the ability of small oligomeric fragments of a prion fibril core structure to maintain their conformational integrity. Dimers were unstable, while trimers maintained substantial intermolecular β-sheets. Further increases in size helped preserve major structural motifs and the prion templating surfaces. Simulations at elevated temperatures showed that 8- and 25-mers had no tendency to fragment within 1-2 µs. Our findings suggest that short fragments of cross-β amyloid fibrils can be stable enough to account for bioactive oligomeric species detected in proteinopathy patients.

Grace Hallinan, PhD, Indiana University School of Medicine, Indianapolis, IN

Abstract: Cryo-EM structures of PrP and tau filaments from GSS F198S
Misfolding and aggregation of certain proteins are hallmarks of many neurodegenerative diseases, including Prion-Protein Amyloidoses, which are dominantly inherited diseases associated with missense, nonsense, and insertion mutations in the PRNP gene. In addition to deposition of aggregated prion protein (PrP), some PRNP mutations also cause tau protein accumulation throughout the brain. Two such mutations are a nonsense mutation in PRNP (Q160X) leading to early termination of PrP translation, causing Prion-Protein cerebral amyloid angiopathy, and a missense mutation in PRNP (F198S) causing Gerstmann-Sträussler-Scheinker (GSS) disease. The clinical and neuropathologic phenotypes associated with these mutations are different; however, neuropathologic analyses show extracellular PrP plaques alongside intracellular tau inclusions in both.
Using cryogenic-electron microscopy (cryo-EM), we determined the structures of tau and prion protein filaments isolated post-mortem from the brain of symptomatic PRNP F198S and Q160X mutation carriers. We found that the tau in these diseases is identical to tau in Alzheimer disease (AD), which suggests there may be similar mechanism(s) by which an extracellular amyloid, like amyloid beta in AD or amyloid PrP in GSS, lead to identical misfolding of tau. We also discovered the first human ex-vivo structure for PrP. The core of PrP filaments in GSS (F198S) consists of 62 amino acids, adopting a spiral fold comprised of nine short β-strands. We determined that PrP filaments are composed of dimeric, trimeric and tetrameric left-handed protofilaments with their protomers sharing a common protein fold. This fold was the same regardless of the patient’s amino acid polymorphism at codon 129; we saw identical folding in 129MV and 129VV patients.
These novel findings highlight the urgency of extending our knowledge of filament structures that may underlie distinct clinical and pathologic phenotypes of human neurodegenerative diseases. These structures may enable the generation of positron emission tomography tracers and therapeutic interventions for PrP and tau.

Szymon W. Manka, PhD, MRC Prion Unit, Institute of Prion Diseases, UC London, London, England

Biography: Dr. Szymon W. Manka obtained his Ph.D. in Biochemistry and Molecular Biology from Imperial College London. In his thesis, Szymon proposed a mechanism of collagen degradation by the prototypic human collagenase MMP-1. He continued his scientific journey at the University of Oxford and Birkbeck College London, specializing in structural biology and biophysics of helical assemblies and their binding partners. His postdoctoral work has provided insights into the molecular mechanisms governing cell division, neuronal cell migration, and brain development. In 2019, Szymon established a cryo-electron microscopy (cryo-EM) laboratory at the University College London (UCL) Institute of Prion Diseases. He currently serves as a UK Medical Research Council (MRC) Career Development Award Fellow and Senior Lecturer at Imperial College London and his lab focuses on defining the structural basis of prion pathogenicity.

Abstract: Spying on prion strains in real time and across scales in cultured cells
How infectious prion fibrils (PrPSc) enter cells and replicate is poorly understood. They require access to PrP substrate in a certain cellular or extracellular niche to grow. They then must undergo fission in a certain niche to generate infectious seeds that can somehow be passed on and spread among cells. To gain further insights into these events, we aimed to capture them in real time using total internal reflection fluorescence (TIRF) microscopy. This required fluorescent labeling of the cellular prion protein (PrPC) in a way that supports prion propagation (conversion of PrPC into PrPSc) during live cell imaging, which current antibody- or fluorescent fusion protein-based methods cannot guarantee. To address this, we expanded the genetic code of prion-susceptible mouse neuroblastoma cells to site-specifically incorporate a fluorophore-taggable non-canonical amino acid (ncAA) into PrP through amber suppression. We established a novel cell-based platform for live monitoring of prion infection. Our engineered fluorescent PrPC (F-PrPC), with only a single amino acid modification, exhibits physiological distribution in the cell and appears to convert into fluorescent prions (F-PrPSc) upon infection with ex vivo prion seeds. This system will be instrumental in identifying key stages of prion propagation, enabling close examination using super-resolution, single-molecule localization microscopy, and cryo-correlative light, electron, and X-ray microscopy (cryo-CLEXM), providing deeper insights into the nano-environments where prions establish infection.

Simon Mead, PhD, Clinical Professor, MRC Prion Unit, Institute of Prion Diseases, UC London, London, England and National Prion Clinic, UC London, London, England (Moderator)

Biography: After medical training at Cambridge and Oxford Universities and a PhD in the genetics of prion diseases at Imperial College London, Simon Mead is a consultant neurologist and Clinical Lead of the UK National Prion Clinic based at the National Hospital for Neurology and Neurosurgery, UCLH. Also working at the UK Medical Research Council’s Prion Unit where he is Deputy Director, his research interests include treatments and preparations for clinical trials in CJD and other human prion diseases, the discovery of genetic and epigenetic factors that cause or modify prion disease. He was made a Professor at UCL in 2014, NIHR Senior Investigator in 2018.

Abstract: Discovery and functional genetics analysis of human prion disease modifiers
Human prion diseases have strong genetic determinants of both risk and clinical phenotypes. In this talk I will summarise work in recent years from a consortium of researchers who have collected more than 6000 samples from patients with probable or definite sporadic Creutzfeldt-Jakob disease (sCJD) and Inherited Prion Diseases (IPD), predominantly in populations with European ancestries. We have done genome wide association studies (GWAS) of risk and clinical phenotype in sCJD, GWAS of age at clinical onset in IPD, multiple transcriptome and proteome-wide association studies and Bayesian genetic colocalization analyses (coloc) between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. Systematic gene prioritization and nomination of prioritized sCJD risk genes with risk-associated molecular mechanisms. The main determinant of risk and clinical phenotype is the well-known coding sequence of PRNP, however other risk loci and mechanisms are becoming clear. These include increased expression of Syntaxin-6 (STX6) and protein disulfide isomerase A4 (PDIA4) in the brain, reduced expression of Mesencephalic Astrocyte Derived Neurotrophic Factor (MANF), and a missense variant in the Galactose-3-O-Sulfotransferase 1 (GAL3ST1) gene. These genes involve intracellular trafficking, sulfatide metablism and the unfolded protein response and connections are starting to emerge. The results of manipulation of STX6 and GAL3ST1 in disease models will be described. In mouse, Stx6 knockout reduced the risk of prion disease transmission when the dose of inoculum was limited. In cellular models, Stx6 manipulation led to a redistribution of abnormal PrP, and altered prion export. Hemizygous knockout of Gal3st1 did not alter mouse prion disease incubation times in classical transmission experiments. Human omic studies allow for the discovery of hitherto unexpected causal mechanisms in prion diseases. Whether these findings will inspire new therapeutic targets is unclear at present. 

Eric Minikel, PhD, Senior Group Leader, Broad Institute of MIT and Harvard, Cambridge, MA

Biography: Eric is Sonia Vallabh, PhD’s husband. He followed Sonia into biomedicine to join the quest for a cure. He trained on human genomics in the MacArthur Lab and on chemical biology in the Schreiber Lab and earned his Ph.D. in Biological and Biomedical Sciences from Harvard. He blogs at CureFFI.org and tweets as @cureffi.

Abstract: Unifying lessons from genetically guided drug discovery for neurodegenerative diseases
Only ~10% of drug candidates that reach clinical development are ultimately approved, and the success rate is particularly low in neurodegenerative diseases. Human genetic evidence — when drug's molecular target and its indication are causally
 linked by human genetic association studies — is one of the few factors proven to improve success rates in drug development. The relative value and pitfalls of evidence from Mendelian disease versus genome-wide association studies (GWAS) will be discussed,
 as well as the distinction between symptom-managing versus disease-modifying therapies and how these may be distributed differently in neurology versus other therapy areas. Special considerations for neurodegenerative disease include the risk of misalignment
 between the disease stage at which risk variants act and the disease stage at which trials are conducted, and the temptation to pursue therapeutic targets perceived as having cross-disease relevance that are not actually backed by genetic evidence. The greatest
 opportunity for shared wins between Alzheimer's disease and related dementias, including prion disease, may lie not in the drugging of shared molecular targets, but in the development of biomarkers, model systems, clinical pathways, and above all, platform
 technologies and delivery systems, that will have broad relevance across these disorders.

Allison Kraus, PhD, Associate Professor, Division of Experimental Pathology, Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH

Piero Parchi, MD, PhD, Associate Professor, Department of Biomedial and Neuromotor Sciences, University of Bologna, Bologna, Italy

Biography: In his scientific career, Prof. Piero Parchi has developed extensive experience in the field of human neurodegenerative diseases contributing to neurobiology, neuropathology, and clinical studies. He trained in Neurology in Italy and Molecular and Morphological Neuropathology in the United States at CWRU and in Germany at the Ludwig Maximilian University. During his research activity in the United States, he proposed a classification of Creutzfeldt-Jakob disease, the most frequent human prion disease, which is still recognized and internationally referenced. After his postdoctoral fellowship and return to Italy in 2000, he started a new laboratory from scratch and formed a research team. Since then, Piero Parchi and his team have conducted studies in the fields of neurology, clinical neurobiology, and neuropathology. His research interests are mainly focused on prion and prion-like neurodegenerative diseases and aim to explore the molecular basis of phenotypic variability and the development and validation of biomarkers for early clinical diagnosis and prognostic evaluation. In the latter area, Piero Parchi’s team has recently contributed significantly to validation in the clinical setting of seed amplification assays for the early diagnosis of prion disease and Lewy body disease.

Abstract: α-Synuclein SAA: A highly specific marker for the early diagnosis and stratification of patients with synucleinopathies
Lewy body disease (LBD), the second most prevalent neurodegenerative disorder after Alzheimer’s disease (AD), is characterized by the intraneuronal accumulation of misfolded α-synuclein (α-syn) in the form of Lewy bodies. It is primarily the pathological hallmark of Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB), but it also constitutes a frequent co-pathology in patients with AD. Recently, α-syn seed amplification assays (SAA) such as Real Time Quaking Conversion (RT-QuIC) exploiting the prion-like properties of α-syn to amplify and detect misfolded α-syn from accessible fluids and tissues have been successfully exploited by different laboratories using alternative protocols. We have applied the α-syn RT-QuIC SAA protocol developed by Byron Caughey’s lab to large patient cohorts and individuals with prodromal or pre-clinical disease, some with neuropathological verification, significantly contributing to establishing the assay as the first accurate pathology-specific biomarker of LBD. Recently, we have also exploited the α-syn RT-QuIC SAA to provide quantitative values of seeding activity and found positive associations with the LBD stage and burden and clinical variable of disease progression and severity. These findings raise hope for the future use of α-syn RT-QuIC SAA not only as a diagnostic marker but also as a surrogate marker of response to experimental drugs in clinical trials or as a prognostic marker in clinical practice.

Claudio Soto, PhD, Director, The George and Cynthia W Mitchell Center for Alzheimer's Disease and Other Brain Related Illnesses, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX (Moderator)

Biography: Dr. Soto is the Huffington Distinguished University Chair, Professor of Neurology and Director of the Mitchell Center for Alzheimer’s Disease and Related Brain Disorders at The University of Texas Health Science Center at Houston, McGovern Medical School. Dr. Soto has been working in the field of neurodegenerative diseases, in particular in Alzheimer's, Parkinson’s and prion diseases for the past 30 years and has made several important discoveries both to the basic science understanding of these diseases and to the translation of this knowledge into novel strategies for treatment and early diagnosis. He invented and developed the Protein Misfolding Cyclic Amplification (PMCA), (also known as SAA and RT-QuIC) technology for ultra-sensitive detection of misfolded proteins and beta-sheet breaker approach to produce therapeutic compounds for various protein misfolding disorders. He also contributed to understand that protein misfolding diseases have the intrinsic ability to be transmissible and that misfolded protein aggregates can adopt alternative conformations, usually referred as conformational strains and lead to different diseases. Also, he has been studying the use of induced pluripotent stem cells for regenerative therapy as well as developing novel cellular (including 3D cerebral organoids) and animal models of these diseases. Dr. Soto has published more than 230 peer review publications, which have been cited more than 35,000 times (H index 92). According to Google scholar, 87 articles have >100 citations, 48 have >200, 11 have >500 and 5 have >1000. Dr. Soto has received >60 million dollars funding from NIH over the past 20 years.

Abstract: Seed Amplification Assays: From Prions to ADRDs and Parkinsonism

Michel Goedert, FRS, FMedSci, Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, England

Biography: Michel Goedert, MD, PhD, Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
Michel Goedert is a Programme Leader at the MRC Laboratory of Molecular Biology, where he works on the abnormal filamentous amyloid inclusions that characterise many human neurodegenerative diseases. Most of Michel’s research has been on the proteins tau and alpha-synuclein. Michel is a member of the European Molecular Biology Organisation, a Fellow of the Royal Society and a Fellow of the UK Academy of Medical Sciences.

Abstract: Cryo-EM structures of amyloid filaments from the human brain
We are using electron cryo-microscopy (cryo-EM) to determine the structures of amyloid filaments from the brains of individuals with neurodegenerative diseases. Formation of these filaments is believed to be of central importance for neurodegeneration. I will give an overview of our work on tau, Abeta and alpha-synuclein filaments. So far, each sporadic condition with abundant filamentous tau and alpha-synuclein inclusions has been characterised by a specific fold, but the same filament fold can be found in several different diseases. For instance, the tau filament fold of chronic traumatic encephalopathy (CTE) is also found in subacute sclerosing panencephalitis (SSPE), amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC) and vacuolar tauopathy (VT). Differences between folds are found in different diseases, but not in different individuals with the same disease. In future, we aim to form the human brain amyloid folds under defined experimental conditions. I will discuss our ongoing work on the formation of the Alzheimer and CTE tau folds using expressed recombinant proteins.

Debbie Yobs, President and Executive Director, CJD Foundation (Moderator)

Families: Trevor Baierl, Nick De Maggio, Pamela Fear, Amanda Kalinsky, Vicki Qualley

Bernardino Ghetti, MD, Distinguished Professor, Indiana University School of Medicine, Indianapolis, IN

Abstract: Hereditary PrP Amyloidoses: Intersections and Overlaps
Over the past 48 years at the Indiana University Dementia Laboratory, the focus in prion disorders has been on prion protein (PrP) amyloidoses. In an effort to consider the implications of intersections between and overlaps with as they relate to PrP amyloidoses and amyloid β amyloidosis, i.e. Alzheimer disease (AD), we analyzed neuropathologically tissues from patients belonging to selected kindreds. The disease phenotypes in these kindreds were first described by our laboratory’s team. As intersection means sharing one point in common between two lines, we discuss about selected misfolded proteins as the points of intersection relative to the phenotypes of the selected hereditary PrP amyloidoses and AD. Intersection by misfolded proteins may also exist as a phenomenon occurring in the presence of co-pathologies. As for intersections, overlaps may also occur when two distinct pathologic processes that take place as a result of different pathogenetic mechanisms coexist. The phenotypes of PrP amyloidoses, which we focus on, are those of two neurodegenerative dementias, namely Gerstmann-Sträussler-Scheinker disease associated with the mutation PRNP F198S and the PrP cerebral amyloid angiopathies associated with the mutations PRNP Y145X and PRNP Q160X. To illustrate the concepts of intersection and overlap, we consider the following proteins: PrP, amyloid β, tau, α-synuclein and TMEM106B. For the concept of overlap, we consider anatomical, histological, cellular, and structural features, primarily at the levels of the cerebral and cerebellar cortices as well as ependyma. It must be distinguished whether intersections or overlaps occur as independent phenotypic characteristics rather than the result of the presence of co-pathologies. The co-pathologies may be caused by dominant or recessive genes that differ from those operating in the selected prion disease or from known genetic risk factors. Furthermore, intersections or overlaps may occur in prion diseases and AD via environmental causes.

Gabor G. Kovacs MD, PhD, Professor, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Moderator)

Biography: Gabor G. Kovacs MD PhD is Professor of Neuropathology and Neurology at the University of Toronto.
He is Consultant Neuropathologist and Neurologist at the University Health Network (UHN) and a Principal Investigator at the Tanz Centre for Research in Neurodegenerative Disease. Dr. Kovacs holds the Rossy Chair in PSP Research at UHN and is the Co-Director of the Rossy Program for Progressive Supranuclear Palsy Research.
Dr. Kovacs completed his medical training at the Semmelweis University (Budapest, Hungary) where he specialized in Neurology and Neuropathology and obtained a PhD in Neuroscience. From 2004 to 2007, he was the Head of the Department of Neuropathology at the National Institute of Psychiatry and Neurology in Budapest, Hungary. From 2007 to 2019, he was an Associate Professor at the Institute of Neurology at the Medical University of Vienna, Austria. He was the leader of the Hungarian (2004-2019) and Austrian (2011-2019) Reference Center for Human Prion Diseases. Dr. Kovacs has also trained at Indiana University (2007) and University of Pennsylvania (2016 and 2017) as a visiting professor/scholar.
His major research interest is the neuropathology of neurodegenerative diseases to identify early biomarkers and therapy targets. His achievements include first descriptions, characterization and pathogenic elucidation of several poorly recognized neurological diseases, including frontotemporal dementia with globular glial inclusions and ageing-related tau-astrogliopathy (ARTAG). He coordinated a study and described the sequential distribution of tau pathology in ARTAG and progressive supranuclear palsy. In addition, Dr. Kovacs has made fundamental descriptions on pathogenic, genetic, neuropathologic and epidemiologic aspects of human tau, alpha-synuclein and prion protein-related diseases. He has published more than 350 peer-reviewed papers and edited three books on Neuropathology. 

Abstract: Current concepts of mixed pathologies in neurodegenerative diseases
Neurodegenerative diseases are a pathologically, clinically, and genetically diverse group of disorders without effective disease-modifying therapies. Pathologically, these disorders are characterised by disease-specific protein aggregates in neurons and/or glia and referred to as proteinopathies. Sequential distribution patterns of protein inclusions throughout the brain have been described. Rather than occurring in isolation, it is increasingly recognised that combinations of one or more proteinopathies with or without cerebrovascular disease frequently occur in individuals with neurodegenerative diseases. In addition, complex constellations of ageing-related and incidental pathologies associated with tau, TDP-43, Aβ, α-synuclein deposition have been commonly reported in longitudinal ageing studies and also in hereditary conditions. standardization in the nomenclature used to describe multiple proteinopathies is needed. Careful discrimination is required to distinguish neurodegenerative proteinopathies versus ageing-related pathologies, and in particular what pathological burden is considered sufficient to cause clinical symptoms. A number studies have suggested common pathologic mechanisms and/or interaction of pathological proteins in neurodegenerative diseases; however, these have to be carefully evaluated whether there is any possibility at all for interaction in brain regions. Cases with mixed pathologies might show a different clinical course, which has prognostic relevance and obvious implications for biomarker and therapy development, and stratifying patients for clinical trials.

Rodrigo Morales, PhD, Professor, The George and Cynthia W Mitchell Center for Alzheimer's Disease and Other Brain Related Illnesses, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX

Biography: Dr. Rodrigo Morales received his doctoral degree (PhD) from University of Chile in 2009 (thesis work fully performed at The University of Texas Medical Branch at Galveston). Currently, he is an Associate Professor at The University of Texas Health Science Center at Houston (UTHealth). His main research interests involve studying the molecular basis of infectious prions, specifically prion strain diversity and interspecies transmission dynamics. He is also leading several funded programs dedicated to study the role of amyloid beta protein in Alzheimer’s disease and the pathological consequences of the cross-talk between different misfolded proteins. He has published more than 50 articles in the field of protein misfolding disorders.

Abstract: Cross-seeding of misfolded proteins: potential implications in disease
Protein misfolding co-pathologies have been long described as a relevant feature in disease scenarios. Moreover, the co-existence of misfolded proteins is mostly associated with faster progressions and exacerbated clinical signs. Although several hypotheses have been formulated to explain these events, protein misfolding cross-seeding seems to partially explain some of these pathological interactions. In this talk, we will discuss the molecular bases of protein misfolding cross-seeding and examples in the context of human pathology, including studies in cell-free systems, cell cultures, and animal models. Moreover, the potential interaction between mammalian and bacterial amyloids in the context of disease will also be discussed.

Brian Appleby, MD, Director, National Prion Disease Pathology Surveillance Center, Case Western Reserve U School of Medicine, Cleveland, OH (Moderator)

Biography: Dr. Appleby is a neuropsychiatrist with primary clinical and research interests in atypical dementias.  He received a B.A. in biology and philosophy from Goucher College and a M.D. from Georgetown University School of Medicine.  He completed a psychiatry residency and geriatric psychiatry fellowship at The Johns Hopkins Hospital. He is Professor of Neurology, Psychiatry, and Pathology at Case Western Reserve University.  He serves as the Director of the National Prion Disease Pathology Surveillance Center, Medical Director of the CJD Foundation, and Chair of the Cleveland Alzheimer’s Association Chapter’s Professional Advisory Board.  He has several leadership roles in the Cleveland Alzheimer’s Disease Research Center, including leader of its Clinical Core and Co-Leader of its Neuropathology Core.

Gregg Day, MD, Department of Neurology, Mayo Clinic, Jacksonville, FL

Abstract: Clinical Applications of Biomarkers in Prion Disease
Biomarkers are routinely applied to support disease-specific diagnoses, inform contributors to disease, and predict outcomes in patients with neurodegenerative diseases. In prion disease, increasingly sensitive and specific neuroimaging and biofluid biomarkers have revolutionized the diagnostic approach to patients with suspected prion disease, supporting early and accurate diagnoses, aiding detection of prion disease mimics (including patients with potentially treatment-responsive causes), and enabling enrollment in putative prion disease-modifying clinical trials. Yet even the best biomarkers are not perfect—emphasizing the need to interpret and apply biomarkers in the context of the clinical history, examination, and other available information. This presentation will review the sensitivity and specificity of accessible diagnostic and prognostic biomarkers, with focus on optimizing application of findings to improve clinical diagnoses, support counselling, and advance the care of patients with suspected prion disease. Novel applications of established biomarkers of common neurodegenerative diseases (Alzheimer disease and related dementias) in the evaluation of patients with prion disease will also be discussed.

Richard Knight, BA, BM BCh, FRCP(E), Chair, CJD Support Network, U.K. and Emeritus Professor of Clinical Neurology, The University of Edinburgh, Edinburgh, Scotland

Biography: Professor Richard Knight received his BA degree in philosophy, politics, and economics at Oxford University in 1972, his medical degree in 1977, his postgraduate medical qualification in 1980 and became a Fellow of the Royal College of Physicians of Edinburgh in 1993.
Professor Knight is a Clinical Neurologist  in the UK National CJD Research & Surveillance Unit and is an Emeritus Professor of Clinical Neurology at the University of Edinburgh. He has had a long involvement with CJD lay and charity organizations; currently being Chair of the UK National CJD Support Network Management Committee, a Director of the CJD International Support Alliance and an International Champion for the CJD Support Group Australia.
Professor Knight’s main research interests have centered on the epidemiology, clinical features and diagnosis of prion disease. Outside of medicine, he has interests in philosophy, physics and mathematics, obtaining his BSc (in Physics/Maths) in 2019.

Abstract: Commonality in the clinical approach to ADRD and Prion Disease
Prion diseases have generally been considered separately from ADRD, reflecting their relative rarity and much-studied transmissibility. However, they share a protein-misfolding, neurodegenerative nature with ADRD, with the occurrence of genetic and sporadic forms. There is also accumulating evidence for at least some common transmissibility concerns. Additionally, the protein disease mechanisms they have in common, have informed similar approaches to developing diagnostic tests. From the practical clinical point of view, in terms of presentation, diagnostic process, symptom management, and care, there are many common themes. In the early clinical stages, all of these diseases may be part of the differential diagnosis, and the initial investigations are generally the same, as are the clinical skills required for proper assessment. The management and care of such brain illnesses reflects the resultant clinical features rather more than their specific cause. Finally, as we have at least the dawn of possible disease-modifying treatments, the therapeutic approaches have much in common.

Karen Ashe, MD, PhD, Professor, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN

Biography: Dr. Karen Ashe, MD, PhD, is a neurologist and researcher at the University of Minnesota known for her research on Alzheimer's and other forms of dementia.  Her pioneering work in identifying mutations causing familial prion diseases and in developing transgenic mice with inherited prion diseases transformed how scientists study neurodegenerative diseases.  Mouse models from her laboratory are widely used by researchers worldwide.  Dr. Ashe currently leads collaborative projects focused on developing therapies targeting memory loss and dementia, underscoring her commitment to advancing treatment options for these conditions.

Abstract: The Aβ Oligomer Aβ*56 Appears to Assemble into Hollow Spheroid Structures
Aβ*56 is a water-soluble Aβ oligomer that has been detected by several independent groups in at least four Alzheimer’s disease (AD) mouse models and in humans with AD.  When Aβ*56 is isolated from Tg2576 brain and injected into healthy rodents, it impairs memory function.  In Tg2576, J20, and APPTTA AD mouse models, Aβ*56 corresponds more closely to memory loss than neuritic plaques, and in humans with AD, it inversely correlates with cognitive decline, independent of amyloid plaques (I. Lapcinski, K. Ashe, and P. Liu, manuscript in preparation).  
Key features of Aβ*56 include: 1) a consistent mass of ~56 kDa, observed in both denaturing sodium dodecyl sulfate (SDS)-PAGE and non-denaturing size-exclusion chromatography (SEC), which reflects its unique stability in the ionic detergent SDS compared to other high molecular-weight Aβ oligomers; 2) affinity for A11 conformational antibodies, which target non-fibrillar oligomeric assemblies; and 3) the presence of canonical Aβ(1-40) and/or Aβ(1-42) peptides.  
Here, we present a preliminary structural analysis of Aβ*56 purified from Tg2576 mice younger than 12 months of age, before neuritic plaque formation.  Proteins in detergent-free, aqueous brain extracts eluting at ~56 kDa on SEC were immunoprecipitated using D8Q7I antibodies specific to the C-terminus of Aβ(x-40).  After fractionation by SDS-PAGE, the ~56-kDa entity was electro-eluted from excised gel slices.  This material, fractionated by native-PAGE, revealed three peaks at 58 kDa, 208-260 kDa, and 552-934 kDa.  Transmission-electron micrographs showed circular and ovoid particles with denser rims than centers, and there were no filamentous structures.  The diameters of 441 particles formed four distinct groups: 7.6 nm, 10.5 nm, 13.4 nm, and 15.7 nm.  Negative-stain images processed with CryoSPARC identified 1,109 two-dimensional particles, 834 of which were classified into four groups of three-dimensional particles resembling hollow spheroids with the following volumes: 99-187 nm3, 269-342 nm3, 458-670 nm3, and 690-1270 nm3.

Melanie Meyer-Lüehmann, PhD, Professor, Department of Neurology and Neuroscience, University of Freiburg, Freiburg, Germany

Biography: Dr. Meyer-Luehmann is a Professor of Functional Restoration in the CNS at the University of Freiburg in Germany. She obtained her PhD in Neurobiology from the University of Basel in  Switzerland before moving with her doctoral supervisor Prof. Mathias Jucker for a short Postdoc to the University of Tübingen, Germany. Then she conducted postdoctoral research in the lab of Prof. Brad Hyman at Harvard Medical School in Boston, USA. She started her own independent group in Germany at the Ludwig-Maximilians-University in Munich and was appointed Professor of Functional Restoration in the CNS at the Medical Center of the University of Freiburg in 2011. The research focus of her group is to study pathomechanisms underlying neurodegenerative diseases with a particular focus on Alzheimer’s disease. Currently she is investigating protein aggregation mechanisms and Aβ spreading routes. 

Abstract: Amyloid-beta spreading from the olfactory bulb
In general, the aggregation of Aβ is considered an essential early trigger in AD pathogenesis that leads to neurofibrillary tangles, neuronal dysfunction and dementia. Olfactory dysfunction is an early symptom of dementia and senile plaques are encountered in the olfactory bulb of AD patients and in mouse models of AD. However, mechanisms involved in spreading of Aβ seeds from the olfactory bulb are still elusive. Our data so far show that Aβ seeding in the olfactory bulb leads to olfactory deficits and that there is a distinct pattern and Aβ spreading route from the olfactory bulb. 

Nathalie Van Den Berge, MScEng, PhD, Associate Professor, Department of Clinical Medicine - Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Aarhus, Denmark

Biography: Van Den Berge pursued her education in Belgium and U.S.A. in three different engineering disciplines: construction (M.Sc.Eng.), industrial (M.Sc.Eng.) and biomedical (PhD). Subsequently, she moved to Denmark to join Professor Per Borghammer’s group as postdoc. Today, Van Den Berge (age 38) is a principal investigator at the department of Clinical Medicine, Aarhus University. Driven by her passion to uncover complex prion-like mechanisms underlying Lewy body disorders, Van Den Berge decided to pursue a career in multi-disciplinary research, which encompassed health, natural and engineering sciences. Van Den Berge has made great contribution to Lewy body disease research by developing the first body-first Lewy body disease animal model (Acta Neuropathol 2019; Brain 2021). Despite the increasing evidence that Lewy body disease may begin outside of the brain years before motor symptoms appear, most research has focused on modeling the disease in the brain only. Van Den Berge’s body-first model closely replicates the human disease and involves peripheral organs and old age, providing a breakthrough in the field. This accomplishment has opened a new avenue of research that may provide invaluable insight into the early stages of Lewy body disease subtypes, and help to identify new subtype-specific biomarkers and disease-modifying treatment targets.

Abstract: Prion-like phenomena and protein strain variability in Lewy body disorders
Lewy body disorders (LBD) like Parkinson’s disease and Dementia with Lewy Bodies are characterized by pathological misfolding and aggregation of the protein alpha-synuclein (asyn), which causes progressive neurodegeneration in the brain and body and subsequent motor and non-motor symptoms. Asyn aggregates can propagate transsynaptically along the brain-body axis, affecting multiple organs and propagating through multiple cell types. Next to a damaged brain, it is wellknown that LBD patients exhibit extensive nerve damage to peripheral organs, such as in the heart and the gut, causing debilitating non-motor symptoms up to 20 years before motor symptoms occur. This early ‘premotor´ disease phase is highly heterogeneous across patients with variable involvement of different neuronal systems, challenging diagnosis.  Accumulating imaging and neuropathological evidence points towards the existence of two LBD subtypes where early disease heterogeneity seems to be associated to disease onset site (body vs. brain) and consequent prionlike spread through the autonomic connectome. Furthermore, increasing data suggest that clinical heterogeneity seen in patients can be explained by the presence of distinct asyn strains, which exhibit variable morphologies. Importantly, the cellular environment is known to impact strain morphology. We hypothesize that the changing cellular environment during brain-to-body or body-to-brain asyn propagation influences strain morphology. Here, we use rodent models of body-first and brain-first LBD to determine if asyn strain morphology and disease onset site are interdependent determinants of early LBD phenotypes. The identification of subtype-specific early disease indicators and subtype-specific asyn strain conformations may enable accurate diagnosis of different LBD subtypes in the early disease stage. This is especially beneficial in the body-first subtype with early intervention in the pre-motor phase, prior to damage to the brain.

Amanda L. Woerman, PhD, Associate Professor, Prion Research Center, Department of Microbiology, Immunology, and Pathology, College of Vetrinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO (Moderator)

Biography: Amanda L. Woerman received her B.A. in Botany/Microbiology and Politics & Government from Ohio Wesleyan University in 2008, and her PhD in Molecular Medicine from The George Washington University in 2013. Working with Dr. David Mendelowitz, she designed the first animal model of perinatal exposure to the air pollutant sulfur dioxide and identified the mechanism by which it produces tachycardia and cardiovascular disease. In July 2013, Amanda joined Dr. Stanley Prusiner’s laboratory at UCSF as a postdoctoral fellow, where she developed cellular assays for tau and alpha-synuclein prions, which she employed to investigate the role of prion strains in neurodegenerative disease. Amanda is currently an Associate Professor at the Prion Research Center at Colorado State University, where her lab investigates tau and alpha-synuclein strain biology, pathogenesis, and adaptation.

Brian Appleby, MD, Director, National Prion Disease Pathology Surveillance Center, Case Western Reserve U School of Medicine, Cleveland, OH

Biography: Dr. Appleby is a neuropsychiatrist with primary clinical and research interests in atypical dementias.  He received a B.A. in biology and philosophy from Goucher College and a M.D. from Georgetown University School of Medicine.  He completed a psychiatry residency and geriatric psychiatry fellowship at The Johns Hopkins Hospital. He is Professor of Neurology, Psychiatry, and Pathology at Case Western Reserve University.  He serves as the Director of the National Prion Disease Pathology Surveillance Center, Medical Director of the CJD Foundation, and Chair of the Cleveland Alzheimer’s Association Chapter’s Professional Advisory Board.  He has several leadership roles in the Cleveland Alzheimer’s Disease Research Center, including leader of its Clinical Core and Co-Leader of its Neuropathology Core.  

John Collinge, CBE, FRS, FMedSci, Director, MRC Prion Unit at UC London, Institute of Prion Diseases, London, England

Biography: John Collinge is Professor of Neurology and Head of the Department of Neurodegenerative Disease at the UCL Institute of Neurology and Director of the UK Medical Research Council (MRC) Prion Unit in London. He also directs the NHS National Prion Clinic at the adjacent National Hospital for Neurology and Neurosurgery. Professor Collinge trained in medicine at the University of Bristol and in neurology at St Mary’s Hospital and the National Hospital for Neurology and Neurosurgery in London. He is committed to highly multidisciplinary research and the seamless integration of basic laboratory and clinical research. He established the MRC Prion Unit at Imperial College London in 1998 where he held the positions of Wellcome Senior Clinical Fellow and then Wellcome Principal Clinical Fellow. His laboratory demonstrated in 1996 that the new human prion disease, variant CJD, was caused by the same prion strain as that causing BSE in cattle and has been responsible for a number of key advances in the field. Professor Collinge has served on numerous Government advisory committees on prion disease at a national, European Union and international level. He is committed to public communication of the Unit’s research and gives many media interviews. He is a Fellow of the Royal College of Physicians, a Fellow of the Royal College of Pathologists, a Founder Fellow of the UK Academy of Medical Sciences and a Fellow of the Royal Society. He was awarded a CBE for services to medical research by HM the Queen. He was also elected an Honorary Fellow of the American Neurological Association.

Abstract: Understanding prions and the implications of iatrogenic Alzheimer’s disease
Human prion diseases were thought unique in having an aetiological triad of inherited, sporadic and acquired forms. The recent ex vivo purification of prions to homogeneity and their structural determination at near atomic resolution by cryogenic electron microscopy confirmed that they comprise amyloid fibrillar assemblies of misfolded cellular prion protein and established the structural basis of prion strain diversity – how protein-only pathogens encode distinct phenotypes. While biophysically, all amyloid by definition can seed its own propagation, not all amyloids can act as an efficient pathogen that can invade and colonise a host, evade its natural defence mechanisms and cause lethal toxicity. Experimental transmissibility of amyloid-beta and other protein assemblies seen in the commoner neurodegenerative diseases is well established in animal models but its relevance for human disease remained controversial. The recognition of human transmission of amyloid-beta pathology from cadaver-derived pituitary growth hormone treatment and neurosurgical dura mater grafting (causing iatrogenic cerebral amyloid angiopathy, iCAA) and now iatrogenic Alzheimer’s disease (iAD) has changed this perspective. That AD (like amyloid-beta CAA) has the full triad of aetiologies characteristic of conventional prion diseases indicates that the principles of prion biology and therapeutic strategies for prion disease have relevance for other neurodegenerative diseases involving the accumulation of diverse assemblies of misfolded host proteins. In addition to important public health considerations to minimise future iatrogenic transmission of amyloid-beta and other proteopathic seeds, this should now allow broader insights from prion biology to be applied to AD and other neurodegenerative diseases.

Claudio Soto, PhD, Director, The George and Cynthia W Mitchell Center for Alzheimer's Disease and Other Brain Related Illnesses, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX (Moderator)

Biography: Dr. Soto is the Huffington Distinguished University Chair, Professor of Neurology and Director of the Mitchell Center for Alzheimer’s Disease and Related Brain Disorders at The University of Texas Health Science Center at Houston, McGovern Medical School. Dr. Soto has been working in the field of neurodegenerative diseases, in particular in Alzheimer's, Parkinson’s and prion diseases for the past 30 years and has made several important discoveries both to the basic science understanding of these diseases and to the translation of this knowledge into novel strategies for treatment and early diagnosis. He invented and developed the Protein Misfolding Cyclic Amplification (PMCA), (also known as SAA and RT-QuIC) technology for ultra-sensitive detection of misfolded proteins and beta-sheet breaker approach to produce therapeutic compounds for various protein misfolding disorders. He also contributed to understand that protein misfolding diseases have the intrinsic ability to be transmissible and that misfolded protein aggregates can adopt alternative conformations, usually referred as conformational strains and lead to different diseases. Also, he has been studying the use of induced pluripotent stem cells for regenerative therapy as well as developing novel cellular (including 3D cerebral organoids) and animal models of these diseases. Dr. Soto has published more than 230 peer review publications, which have been cited more than 35,000 times (H index 92). According to Google scholar, 87 articles have >100 citations, 48 have >200, 11 have >500 and 5 have >1000. Dr. Soto has received >60 million dollars funding from NIH over the past 20 years.

Abstract: Seed Amplification Assays: From Prions to ADRDs and Parkinsonism

Sonia Vallabh, PhD, Senior Group Leader, Broad Institute of MIT and Harvard, Cambridge, MA

Biography: Sonia’s scientific mission is to develop a treatment for prion disease. Besides therapeutic development, her research focuses on the biomarkers, models, tools, assays, patient cohorts, and datasets that will enable translation of therapeutics in the clinic. She earned her Ph.D. from Harvard in Biological and Biomedical Sciences, under Stuart Schreiber. Sonia also holds a J.D. from Harvard Law School. She retrained as a scientist after learning in 2011 that she had inherited the PRNP D178N mutation that causes genetic prion disease, and had claimed her mother’s life the year before. Outside of the lab, Sonia also co-runs the scientific nonprofit Prion Alliance.

Amanda L. Woerman, PhD, Associate Professor, Prion Research Center, Department of Microbiology, Immunology, and Pathology, College of Vetrinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO

Biography: Amanda L. Woerman received her B.A. in Botany/Microbiology and Politics & Government from Ohio Wesleyan University in 2008, and her PhD in Molecular Medicine from The George Washington University in 2013. Working with Dr. David Mendelowitz, she designed the first animal model of perinatal exposure to the air pollutant sulfur dioxide and identified the mechanism by which it produces tachycardia and cardiovascular disease. In July 2013, Amanda joined Dr. Stanley Prusiner’s laboratory at UCSF as a postdoctoral fellow, where she developed cellular assays for tau and alpha-synuclein prions, which she employed to investigate the role of prion strains in neurodegenerative disease. Amanda is currently an Associate Professor at the Prion Research Center at Colorado State University, where her lab investigates tau and alpha-synuclein strain biology, pathogenesis, and adaptation.

Jyan Yu Austin Yang, PhD, Program Director, Neurobiology of Aging and Neurodegeneration Branch, Division of Neuroscience, National Institute on Aging, National Institutes of Health

Biography: Dr. J Austin Yang is a Program Director in Neurobiology of Aging and Neurodegeneration Branch in the Division of Neuroscience. Dr. Yang received his B.A. from National Taiwan University and earned his Ph.D. in Molecular Biology from the University of California, Irvine, where he also completed his postdoctoral training. He was a tenured faculty member at the University of Southern California and the University of Maryland between 2001 and 2015. His primary research and teaching interests were in using mass spectrometry, bioinformatic and proteomic approaches to address many issues in the areas of protein misfolding diseases and cancer biology. Dr. Yang joined the NIA in 2015 and his primary responsibility is managing and developing research programs on the etiology of Alzheimer’s disease.

John Collinge, CBE, FRS, FMedSci, Director, MRC Prion Unit at UC London, Institute of Prion Diseases, London, England

Biography: John Collinge is Professor of Neurology and Head of the Department of Neurodegenerative Disease at the UCL Institute of Neurology and Director of the UK Medical Research Council (MRC) Prion Unit in London. He also directs the NHS National Prion Clinic at the adjacent National Hospital for Neurology and Neurosurgery. Professor Collinge trained in medicine at the University of Bristol and in neurology at St Mary’s Hospital and the National Hospital for Neurology and Neurosurgery in London. He is committed to highly multidisciplinary research and the seamless integration of basic laboratory and clinical research. He established the MRC Prion Unit at Imperial College London in 1998 where he held the positions of Wellcome Senior Clinical Fellow and then Wellcome Principal Clinical Fellow. His laboratory demonstrated in 1996 that the new human prion disease, variant CJD, was caused by the same prion strain as that causing BSE in cattle and has been responsible for a number of key advances in the field. Professor Collinge has served on numerous Government advisory committees on prion disease at a national, European Union and international level. He is committed to public communication of the Unit’s research and gives many media interviews. He is a Fellow of the Royal College of Physicians, a Fellow of the Royal College of Pathologists, a Founder Fellow of the UK Academy of Medical Sciences and a Fellow of the Royal Society. He was awarded a CBE for services to medical research by HM the Queen. He was also elected an Honorary Fellow of the American Neurological Association.

Abstract: Understanding prions and the implications of iatrogenic Alzheimer’s disease
Human prion diseases were thought unique in having an aetiological triad of inherited, sporadic and acquired forms. The recent ex vivo purification of prions to homogeneity and their structural determination at near atomic resolution by cryogenic electron microscopy confirmed that they comprise amyloid fibrillar assemblies of misfolded cellular prion protein and established the structural basis of prion strain diversity – how protein-only pathogens encode distinct phenotypes. While biophysically, all amyloid by definition can seed its own propagation, not all amyloids can act as an efficient pathogen that can invade and colonise a host, evade its natural defence mechanisms and cause lethal toxicity. Experimental transmissibility of amyloid-beta and other protein assemblies seen in the commoner neurodegenerative diseases is well established in animal models but its relevance for human disease remained controversial. The recognition of human transmission of amyloid-beta pathology from cadaver-derived pituitary growth hormone treatment and neurosurgical dura mater grafting (causing iatrogenic cerebral amyloid angiopathy, iCAA) and now iatrogenic Alzheimer’s disease (iAD) has changed this perspective. That AD (like amyloid-beta CAA) has the full triad of aetiologies characteristic of conventional prion diseases indicates that the principles of prion biology and therapeutic strategies for prion disease have relevance for other neurodegenerative diseases involving the accumulation of diverse assemblies of misfolded host proteins. In addition to important public health considerations to minimise future iatrogenic transmission of amyloid-beta and other proteopathic seeds, this should now allow broader insights from prion biology to be applied to AD and other neurodegenerative diseases.

Adriano Aguzzi, Prof. Dr. med., Director, Institute of Neuropathology, University of Zürich, Zürich, Switzerland

Abstract: Functional genomics of the prion life cycle
The Aguzzi lab uses large-scale genetic perturbations to identify factors modifying discrete steps of the prion life cycle. Because most phenotypes relevant to prion biology require complex biochemical assays and are not selectable with surface markers, we resort to arrayed genetic screens in which the activation or ablation of each gene is tested individually. To achieve this, we invented massively parallel plasmid-cloning methodologies to construct arrayed libraries for the genome-wide ablation, activation and epigenetic silencing of human genes (42’378 discrete lentiviral vectors). In an arrayed genome-wide CRISPR activation screen, we identified 80 and 451 up- and downregulators of PrPC expression, respectively. 45 of the 50 strongest modifiers were confirmed in secondary assays. Many of these genes regulated PRNP transcription despite not being canonical transcription factors, and some affected PRNP transcription antithetically to PrPC  protein expression, suggesting posttranscriptional regulation. Other PrPC modifiers impinged on lysosomal degradation, cholesterol metabolism, and mitochondrial function. Surprisingly, the strongest PrPC upregulators affected extracellular matrix (ECM) organization. PrPC levels correlated with ECM abundance, potentially mediated through mechanosensation of gliotic tissue stiffening in prion diseases. Prion entry into cells is a fundamental step of the prion life cycle, and its modulation may impact the establishment and spread of prion infections. A genome-wide CRISPR activation screen for modifiers of prion internalization yielded both expected modulators and novel candidates. Surprisingly, the Bone Morphogenetic Protein (BMP) pathway stood out as the most enriched pathway. Most members of the BMP signal-transduction chain (ligands, receptors, transcription factors) lit up in our screens, with activators and inhibitors leading to increased and decreased prion uptake, respectively. With a synthetic-lethality screen we discovered that ciliogenesis is a crucial contributor to Prion toxicity. We also identified Heterogenous Nuclear Ribonucleoprotein K (hnRNPK) as a factor limiting prion replication. Little is known about its function other that it is essential to cell survival. Using a synthetic-viability CRISPR ablation screen, we found that deletion and overexpression of Transcription Factor AP-2γ (TFAP2C) mitigated and enhanced the death of hnRNPK-ablated cells, respectively. hnRNPK ablation suppressed genes related to lipid and glucose metabolism and enhanced catabolism by modulating mTOR and AMPK, whereas TFAP2C overexpression promoted anabolism. TFAP2C overexpression reduced prion propagation in wild-type cells and neutralized prion accumulation in hnRNPK -suppressed cells. Hence, TFAP2C and hnRNPK are genetic interactors controlling cell metabolism, bioenergy and prion propagation. We are now expanding our approach to more prion-related phenomena, including synuclein phosphorylation after exposure to synthetic preformed synuclein fibrils. Our results showcase the awesome power of unbiased genetic perturbations for the study of neurodegenerative diseases and may enable the identification of novel therapeutically actionable targets.

David Harris, MD, PhD, Department of Biochemistry and Cell Biology, Boston University School of Medicine, Boston, MA

Biography: David A. Harris, M.D., Ph.D. is currently Chair of the Dept. of Biochemistry and Cell Biology at Boston University/Chobanian & Avedisian School of Medicine, a position he has occupied since 2009. He received a B.S. degree from Yale University, and M.D/Ph.D. degrees from Columbia University College of Physicians and Surgeons. He was a faculty member in the Dept. of Cell Biology and Physiology at Washington University School of Medicine from 1990-2009. Dr. Harris’ research program is focused on the molecular and cellular mechanisms underlying prion diseases, including pathways of prion neurotoxicity and therapeutic strategies to treat prion diseases.

Abstract: Prion Synaptotoxic Signaling
The earliest toxic effects of prions occur at the synapse, in particular at postsynaptic dendritic spines, where neurotransmitter receptors and associated cytoplasmic machinery are concentrated. To dissect these early synaptotoxic changes, we use mouse hippocampal neurons cultured at low density in the presence of a glial feeder layer, which facilitates visualization of spines, and subsequent biochemical analysis of neurons. In this system, purified PrPSc causes a rapid (with 4 hrs) retraction of dendritic spines with concomitant abnormalities in synaptic function, long before any compromise of neuronal viability. These effects are strictly dependent on neuronal PrPC expression. Within minutes, PrPSc causes NMDA receptordependent Ca2+ influx and hypersensitivity to externally applied NMDA. This is followed by p38 MAPK activation and collapse of the actin cytoskeleton within spines. Using mouse PrPC mutants (G126V and V208M) that are conversion-resistant, as well as mouse neurons expressing hamster PrPC, and recombinant PrPSc forms with varying levels of infectivity, we have now shown that cellsurface PrPSc is directly responsible for initiation of the prion synaptotoxic signal. Consistent with this conclusion, compounds that prevent accumulation of PrPSc also block synaptotoxicity, but only if applied within the first few hours after PrPSc exposure. We have also carried out transcriptomic and phosphoproteomic analyses of PrPSctreated hippocampal neurons, and processed the results using a chemoproteomics pipeline. This resulted in identification of three key protein kinases (CaMKII, PKC, and GSK3β), pharmacological inhibition of which blocked downstream synaptotoxic events. We hypothesize that newly generated, cell-surface PrPSc activates CaMKII and PKC via NMDA receptormediated Ca2+ influx, resulting in translocation of these kinases to the postsynaptic density. We propose that that the untethered N-terminal domain of cell-surface PrPSc, which is not incorporated into the core amyloid structure, interacts with the lipid bilayer, resulting in alterations in the activity of NMDA receptors and other surface proteins. 

Christina Sigurdson, DVM, PhD, Department of Pathology, Microbiology, and Immunology, University of of California, Davis School of Veterinary Medicine, Davis, CA and Sigurdson Lab, Department of Pathology, University of California, San Diego, San Diego, CA (Moderator)

Biography: Christina Sigurdson is a Professor of Pathology at the University of California, San Diego. She received her D.V.M. at the University of California, Davis, and Ph.D. and anatomic pathology training at Colorado State University (CSU), followed by postdoctoral studies at the University of Zürich with Adriano Aguzzi, where she and her colleagues discovered a key loop region in the prion protein that impacts prion aggregation, species barriers, and strain properties. Her team investigates the structural pathogenesis of prion diseases, particularly the conformational determinants of the prion protein that govern conversion and cell to cell spread, as well as the mechanisms underlying neurotoxicity and synapse loss.

Abstract: Synaptic signaling and excitotoxicity in prion disease
Synapse loss and endolysosomal dysfunction are shared features of prion and other neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. The binding of amyloid-β, tau, and α-synuclein oligomers to PrPC has been increasingly implicated in inducing synaptic dysfunction. For example, oligomer binding reportedly results in PrPC-dependent impairment of long-term potentiation (LTP) and neuritic dystrophy. Yet how PrPC-co-receptor interactions impact signal transduction pathways and contribute to early synaptic failure, neuritic dystrophy, and neuronal loss is unclear. We have developed new knockin mice that express mutant full length Prnp yet develop severe, rapidly progressive neuronal excitotoxicity in the absence of PrP aggregates. Here we use phosphoproteomics to probe the synaptic signaling pathways activated, followed by validation of hits, and finally treatment of mice to alter the disease course.

Ken Chan, PhD, Group Leader, Broad Institute of MIT and Harvard, Cambridge, MA, U.S.A.

Abstract: Developing next-generation human Transferrin receptor-binding AAV capsids for the delivery of therapeutic gene editors to lower prion protein throughout the CNS
Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein that spreads across the brain killing neurons. Currently, there are no effective treatments. In collaboration with labs at the Broad and Whitehead Institute, the Vallabh/Minikel lab has led the development of a prion lowering gene therapy using the recently described epigenetic silencing system CHARM or using a 2-vector base editing strategy. Because prions can be seeded virtually anywhere in the central nervous system (CNS), the success of our gene therapy will require expression of our therapeutic cargo in neurons throughout the CNS. To address this need, the Deverman lab has developed new AAV capsids that are designed for CNS-wide gene delivery in humans via engineered interactions with the human Transferrin receptor (TfR). In humanized TfR expressing mice, these new capsids are capable of transducing the majority of neurons across the CNS after low systemic doses (<1E13 vg/kg), are detargeted from the liver relative to AAV9, and are more effective in evading neutralizing antibodies present in a substantial fraction of patients. In this presentation, we will describe these capsids, their application to PRNP targeted gene therapy.

Holly Kordasiewicz, PhD, Senior Vice President, Neurology, Ionis Pharmaceuticals, Inc., Carlsbad, CA, U.S.A.

Biography: Dr. Holly Kordasiewicz is Senior Vice President of Neurology Research at Ionis Pharmaceuticals, a company that specializes in RNA therapeutics. Dr. Kordasiewicz leads a team focused on identifying RNA therapeutics for currently untreatable neurological disease, including drugs now in clinical trials for Alzheimer’s disease, Parkinson’s disease and prion disease. Dr. Kordasiewicz joined Ionis 13 years ago after completing her post-doctoral fellowship in the laboratory of Dr. Don Cleveland at the University of California at San Diego. Dr. Kordasiewicz began her work on understanding neurological diseases at the University of Minnesota, where she received her Ph.D. in Neuroscience.

Sonia Vallabh, PhD, Senior Group Leader, Broad Institute of MIT and Harvard, Cambridge, MA, U.S.A. (Moderator)

Biography: Sonia’s scientific mission is to develop a treatment for prion disease. Besides therapeutic development, her research focuses on the biomarkers, models, tools, assays, patient cohorts, and datasets that will enable translation of therapeutics in the clinic. She earned her Ph.D. from Harvard in Biological and Biomedical Sciences, under Stuart Schreiber. Sonia also holds a J.D. from Harvard Law School. She retrained as a scientist after learning in 2011 that she had inherited the PRNP D178N mutation that causes genetic prion disease, and had claimed her mother’s life the year before. Outside of the lab, Sonia also co-runs the scientific nonprofit Prion Alliance.

Will P. Daley, PhD, Program Director, Neural Environment Cluster, National Institute of Neurological Disorders and Stroke, National Institutes of Health

National Institutes of Health (Moderator)