Mechanisms of a-Synuclein Aggregation and Toxicity
Abstract
ALPHA-Synuclein is a neurotoxic protein that aggregates to form pathological structures, termed Lewy bodies, in the brains of patients with Parkinson's disease. The aim of this proposal is to understand factors that stimulate or inhibit alpha-synuclein aggregation. In the second year of this proposal we investigated the sequence requirements for binding of iron to alpha-synuclein (Aim 1), the interaction of a-synuclein with different proteins and cofactors (Aim 2&3), and the mechanism of toxicity of alpha-synuclein (Aims 2 and 4). Our work has identified key research outcomes, including: 1) determining that the C-terminus of alpha-synuclein is crucial for metal binding; 2) identifying the proteasomal protein S6' as a protein that binds alpha-synuclein; 3) determining that beta-synuclein can prevent proteasomal inhibition by a-synuclein, probably due to inhibiting binding of a-synuclein to S6'; 4) determining that the E3 ubiquitin ligase, parkin, can prevent toxicity induced (alpha-synuclein in cell culture; 5) determining that alpha-synuclein induces phosphorylation of tau protein in vivo; and 6) comparing the vulnerability of C. Elegans over-expressing of alpha-synuclein to toxicity induced by metals, rotenone and paraquat, and determining that mutations in alpha-synuclein induce selective sensitivity to rotenone.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2003
- Accession Number
- ADA421019
Entities
People
- Benjamin Wolozin
Organizations
- Loyola University New Orleans