Cryo‐ <scp>EM</scp> structure of a novel α‐synuclein filament subtype from multiple system atrophy
Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by accumulation of α-synuclein cross-β amyloid filaments in the brain. Previous structural studies of these filaments by cryo-electron microscopy (cryo-EM) revealed three discrete folds distinct from α-synuclein filaments associated with other neurodegenerative diseases. Here, we use cryo-EM to identify a novel, low-populated MSA filament subtype (designated Type I<sub>2</sub>) in addition to a predominant class comprising MSA Type II<sub>2</sub> filaments. The 3.3-Å resolution structure of the Type I<sub>2</sub> filament reveals a fold consisting of two asymmetric protofilaments, one of which adopts a novel structure that is chimeric between two previously reported protofilaments. These results further define MSA-specific folds of α-synuclein filaments and have implications for designing MSA diagnostics and therapeutics.
Authors
- Nick A. Paras (ORCID: https://orcid.org/0000-0001-5742-4056)
- Eric Tse (ORCID: https://orcid.org/0000-0002-2082-9006)
- Gregory E. Merz (ORCID: https://orcid.org/0000-0003-0842-4935)
- N. Yan (ORCID: https://orcid.org/0000-0003-4978-550X)
- Arthur A. Melo (ORCID: https://orcid.org/0000-0002-9345-1462)
- Stanley B. Prusiner (ORCID: https://orcid.org/0000-0003-1955-5498)
- Daniel R. Southworth (ORCID: https://orcid.org/0000-0001-7108-9389)
- Francisco Candido
- Daniel A. Mordes (ORCID: https://orcid.org/0000-0002-4805-7394)
Institutions
- University of California, San Francisco (US)
- Massachusetts General Hospital (US)
- Institute for Neurodegenerative Disorders (US)
Publication Details
- Journal
- FEBS Letters
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1002/1873-3468.15048
- Citations
- 14
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 5.17
Funders
- Henry M. Jackson Foundation
- National Institute on Aging