LMB Seminar - Transmission of Misfolded Proteins in Neurodegenerative Disorders: A Common Mechanism of Disease Progression

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• Virginia Man-Yee Lee, Center for Neurodegenerative Disease Research, University of Pennsylvania
• Tuesday 08 April 2025, 11:30-12:30
• In person in the Max Perutz Lecture Theatre (CB2 0QH) and via Zoom link https://mrc-lmb-cam-ac-uk.zoom.us/j/99931963515?pwd=6FBGl1amJG2tfvl9ycgkErGpbebGw3.1.

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The formation of misfolded pathological protein aggregates by disease-specific proteins is a common feature of many neurodegenerative diseases and are believed to cause neuronal dysfunction directly or indirectly. Recent studies have strongly implicated cell-to-cell transmission of misfolded proteins through templated recruitment as a common mechanism for the onset and progression of various neurodegenerative disorders. Emerging evidence also suggests the presence of conformationally diverse “strains” for each type of disease protein, which may be another shared feature of pathological aggregates, accounting for the tremendous heterogeneity within each category of diseases. In Alzheimer’s disease and other age-related tauopathies, the normally soluble tau protein accumulates as insoluble neurofibrillary tangles (NFTs), whereas in Parkinson’s disease and other related synucleinopathies, the highly soluble α-synuclein protein are converted to aggregated Lewy bodies (LBs) in neuron and glia and finally TDP -43 forms cytoplasmic inclusions in frontotemporal dementia (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). We have developed in vivo transmission models of tauopathies, synucleinopathies and TDP -43 proteinopathies and have used them to test the “transmission” hypothesis and the “strain” hypothesis in order to elucidate mechanisms of progressive spread of NFTs, LBs and TDP -43 aggregates as well as to explore the molecular basis of strain heterogeneity. Finally, these and other insights on pathogenesis will facilitate the development of novel therapies to treat these late-life neurodegenerative diseases.

This talk is part of the MRC LMB Seminar Series series.

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