Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies - PubMed
12 hours ago
- #Alpha-Synuclein
- #Synucleinopathies
- #Ubiquitin-Proteasomal System
- Alpha-synuclein (αSyn) aggregation is common in neurodegenerative diseases called synucleinopathies, including Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA).
- Different phenotypic characteristics of synucleinopathies may originate from distinct αSyn amyloid structures.
- Pathogenic αSyn from PD, DLB, and MSA show structural differences, as revealed by covalent labeling and limited proteolysis coupled to mass spectrometry (LiP-MS).
- Fibril structural differences correlate with distinct interactomes and neuronal responses, including disease-specific ubiquitination patterns and turnover profiles.
- Components of the ubiquitin-proteasomal system (UPS) interact with αSyn fibrils in a disease/polymorph-specific manner, affecting fibril degradation resistance.
- CRISPR-based genetic modulation identified UPS pathway members (UBE3A, TRIM25, HUWE1, VCP) that reduce αSyn inclusions in a strain-specific manner.
- LiP-MS identified disease-specific protein alterations in postmortem brain homogenates and cells treated with patient-derived fibrils.
- Findings provide insights into disease-specific αSyn accumulation and turnover, offering potential novel drug targets for synucleinopathies.