Killam Seminar Series: How Protein Aggregate Shape Shapes Neurodegeneration

Abstract: The defining feature of synucleinopathies such as Parkinson’s disease (PD) and multiple system atrophy (MSA) is the presence of pathological α-synuclein aggregates within the brain. Evidence is accumulating that α-synuclein can polymerize into structurally distinct “strains” of aggregates. We and others have hypothesized that conformational strains of α-synuclein may be responsible for enciphering disease variability across PD, MSA, and related neurodegenerative disorders. Using a transgenic synucleinopathy mouse model, we have found that distinct disease phenotypes can be induced by injection with different strains of recombinant or human disease-derived α-synuclein aggregates. Recently, we have been investigating how different strains of α-synuclein aggregates may arise in the brain. We have found that considerable structural heterogeneity exists between individual preparations of recombinant α-synuclein fibrils. Moreover, α-synuclein aggregates formed spontaneously in the brains of transgenic mice are conformationally diverse. These results demonstrate that α-synuclein can spontaneously form multiple strains within a consistent molecular environment, which implies that stochastic misfolding into distinct aggregate structures drives the emergence of α-synuclein strains.

Bio: Dr. Watts obtained his PhD in Laboratory Medicine and Pathobiology from the University of Toronto and then conducted postdoctoral research in the lab of Nobel laureate 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 self-propagating, prion-like protein aggregates in Alzheimer’s disease and Parkinson’s disease as well as exploiting the unique properties of the bank vole prion protein to develop improved animal and cellular models of the prion disorders.

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