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bioRxiv · 10.1101/2024.07.01.601365

Structure of a novel α-synuclein filament fold from multiple system atrophy

Yan, N. L.·Candido, F.·Tse, E.·Melo, A. A.·Prusiner, S. B.·Mordes, D. A.·Southworth, D. R.·Paras, N. A.·Merz, G. E.
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Abstract

Multiple system atrophy (MSA) is a synucleinopathy, a group of related diseases characterized by the accumulation of -synuclein aggregates in the brain. In MSA, these aggregates form glial cytoplasmic inclusions, which contain abundant cross-{beta} amyloid filaments. Structures of -synuclein filaments isolated from MSA patient tissue were determined by cryo-electron microscopy (cryo-EM), revealing three discrete folds that are distinct from -synuclein filaments associated with other synucleinopathies. Here, we use cryo-EM classification methods to characterize filaments from one individual with MSA and identify a novel, low-populated MSA filament fold (designated Type I2) in addition to a predominant class comprising MSA Type II2. The 3.3-[A] resolution structure of the Type I2 filament reveals a fold consisting of two asymmetric protofilaments. One is identical to a previously solved Type I protofilament, while the second adopts a novel fold that is chimeric between two previously reported Type I and II protofilaments. These results further define disease-specific folds of -synuclein filaments that develop in MSA and have implications for the design of therapeutic and diagnostic molecules that target disease.

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Yan, N. L., Candido, F., Tse, E., Melo, A. A., Prusiner, S. B., Mordes, D. A., Southworth, D. R., Paras, N. A., Merz, G. E.. 2024-07-04. Structure of a novel α-synuclein filament fold from multiple system atrophy. https://doi.org/10.1101/2024.07.01.601365

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