Identifying Mechanisms and Treatments for Cognitive Decline Following Neurotoxic Alpha-Synuclein Exposure in New Parkinson's Disease Models
Abstract
Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by both motor and cognitive symptoms and the formation of Lewy body inclusions containing aggregated alpha-synuclein protein. Growing evidence suggests that alpha-synuclein aggregation may originate in the gastrointestinal tract and spread to the central nervous system. This gut-to-brain hypothesis of PD suggests that environmental toxin exposures may contribute to the initial formation of alpha-synuclein aggregates in the gut. However, it remains unknown (1) the effects of gut-derived alpha-synuclein on cognitive ability, (2) the mechanisms by which alpha-synuclein spreads, and (3) how novel therapies can target alpha-synuclein induced cognitive decline. In the reporting period, we have completed Specific Aim 1, which is to determine the effects of gut-derived alpha-synuclein on learning and memory cognitive function. Our results showed that gut-derived alpha-synuclein significantly impairs short-term associative learning and memory in our new C. elegans models of PD, recapitulating key cognitive symptoms in PD. The expression levels of the major learning regulator, casy-1, were reduced by PFF treatment, though there is no direct interaction of PFFs with CASY-1 in vivo, suggesting an indirect mechanism by which PFFs disrupt this learning regulator. We are now conducting Specific Aim 2, which is to uncover the mechanisms by which gut-derived alpha-synuclein enters neurons to affect cognition.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1214508
Entities
People
- Danielle Mor
Organizations
- Augusta University