Cryo-EM structure of a novel α-synuclein filament subtype from multiple system atrophy

Nicholas L Yan; Francisco Candido; Eric Tse; Arthur A Melo; Stanley B Prusiner; Daniel A Mordes; Daniel R Southworth; Nick A Paras; Gregory E Merz

doi:10.1002/1873-3468.15048

Cryo-EM structure of a novel α-synuclein filament subtype from multiple system atrophy

FEBS Lett. 2024 Nov 7. doi: 10.1002/1873-3468.15048. Online ahead of print.

Authors

Nicholas L Yan¹, Francisco Candido¹, Eric Tse^{1

2}, Arthur A Melo¹, Stanley B Prusiner^{1

2

3}, Daniel A Mordes^{1

4

5}, Daniel R Southworth^{1

3}, Nick A Paras^{1

2}, Gregory E Merz^{1

2}

Affiliations

¹ Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, CA, USA.
² Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, CA, USA.
³ Department of Biochemistry and Biophysics, University of California San Francisco, CA, USA.
⁴ Department of Pathology, University of California San Francisco, CA, USA.
⁵ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

PMID: 39511911
DOI: 10.1002/1873-3468.15048

Abstract

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 I₂) in addition to a predominant class comprising MSA Type II₂ filaments. The 3.3-Å resolution structure of the Type I₂ 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.

Keywords: cryo‐electron microscopy; multiple system atrophy; neurodegeneration; prion; protein aggregation; α‐synuclein.

Abstract

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