Role of Oligomeric Alpha-Synuclein in Mitochondrial Membrane Permeabilization and Neurodegeneration in Parkinson's Disease
Abstract
Amyloid-like fibrillar aggregate of a-synuclein is a common pathological feature of many neurological disorders, including Parkinson's disease. Interestingly, in vitro studies revealed various non-fibrillar intermediate species during the course of fibrillation, raising a question as to which of these aggregates are pathogenic species. The goal of the current project is to identify and characterize the cellular a-synuclein aggregates and to assess the effects of these aggregates. We have established a biochemical fractionation method to separate alpha-synuclein aggregate subspecies from the cytoplasm. Characterization of these subspecies, using electron microscopy and confocal microscopy, showed that cellular fibrillation also involves non-fibrillar intermediates and that these intermediates need to be accumulated in the pericentriolar region by a microtubule-dependent mechanism in order to form fibrils. We also found that the formation of non-fibrillar intermediates was tightly associated with the fragmentation of the Golgi apparatus, whereas the formation of fibril-rich inclusion bodies occurred after the Golgi fragmentation. Our study suggests that the prefibrillar intermediates can cause impairment of specific cytoplasmic organelles, and we are currently investigating cytotoxic effects of these aggregates in both non-neuronal and neuronal cell types.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2002
- Accession Number
- ADA415960
Entities
People
- Seung-jae Lee