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Cold Spring Harb Perspect Med. 2018 Jul 2;8(7). pii: a024588. doi: 10.1101/cshperspect.a024588.

α-Synuclein: Multiple System Atrophy Prions.

Author information

1
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California 94158.
2
Department of Neurology, University of California, San Francisco, San Francisco, California 94158.
3
Tanz Centre for Research in Neurodegenerative Diseases and Department of Biochemistry, University of Toronto, Toronto, Ontario M5T 2S8, Canada.
4
Daiichi Sankyo Company, Limited, Tokyo, 140-8710, Japan.
5
Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London W6 8RP, United Kingdom.
6
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158.

Abstract

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from the misfolding and accumulation of the protein α-synuclein in oligodendrocytes, where it forms glial cytoplasmic inclusions (GCIs). Several years of studying synthetic α-synuclein fibrils has provided critical insight into the ability of α-synuclein to template endogenous protein misfolding, giving rise to fibrillar structures capable of propagating from cell to cell. However, more recent studies with MSA-derived α-synuclein aggregates have shown that they have a similar ability to undergo template-directed propagation, like PrP prions. Almost 20 years after α-synuclein was discovered as the primary component of GCIs, α-synuclein aggregates isolated from MSA patient samples were shown to infect cultured mammalian cells and also to transmit neurological disease to transgenic mice. These findings argue that α-synuclein becomes a prion in MSA patients. In this review, we discuss the in vitro and in vivo data supporting the recent classification of MSA as a prion disease.

PMID:
28213437
PMCID:
PMC5561534
[Available on 2019-07-02]
DOI:
10.1101/cshperspect.a024588
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