Mechanisms of Aggregated Alpha-Synuclein Induction and Progression

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DESCRIPTION (provided by applicant): Parkinson disease (PD) is the most common movement disorder affecting over one million people in North America alone and results in an insidious reduction in the quality of life and ability to function. A hallmark of PD is the brain accumulation of neuronal cytoplasmic inclusions comprised of the protein a-synuclein, but the presence of α-synuclein brain aggregates is observed in a spectrum of neurodegenerative diseases, including dementia with Lewy body. Several findings suggest that α-synuclein amyloid pathology may spread during disease progression by a self-templating alteration in protein conformation mechanism, however other alternative and/or synergistic biological mechanisms, as supported by our data, could also lead to progression of α-synuclein pathology. From a therapeutic aspect it is critical to determine the relative importance, mechanisms and physiological consequences of the spread of α-synuclein aggregation in disease. It this proposal, two major specific aims are proposed to inform on α-synuclein induced and spread of disease: 1) Using both wild-type and disease causing mutant forms of α-synuclein with unique aggregation properties, we will directly investigated that a-synuclein aggregation can spread within the central nervous system and from the periphery with specific conformational characteristics. 2) We will assess the importance of alternative biological mechanisms including perturbation of the protein network homeostasis, neuronal intermediate filament integrity, neurotoxicity and age-related changes in the induction and propagation of α-synuclein pathology by exogenous a-synuclein challenges. These studies will provide critical insights on the mechanisms and the involvement of α-synuclein aggregation in PD disease progression with the objective of guiding the development of novel therapeutics.