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Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):409-414. doi: 10.1073/pnas.1719369115. Epub 2017 Dec 26.

Familial Parkinson's point mutation abolishes multiple system atrophy prion replication.

Author information

1
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158.
2
Department of Neurology, University of California, San Francisco, CA 94158.
3
Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
4
C. S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114.
5
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA 94158; stanley.prusiner@ucsf.edu.
6
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.

Abstract

In the neurodegenerative disease multiple system atrophy (MSA), α-synuclein misfolds into a self-templating conformation to become a prion. To compare the biological activity of α-synuclein prions in MSA and Parkinson's disease (PD), we developed nine α-synuclein-YFP cell lines expressing point mutations responsible for inherited PD. MSA prions robustly infected wild-type, A30P, and A53T α-synuclein-YFP cells, but they were unable to replicate in cells expressing the E46K mutation. Coexpression of the A53T and E46K mutations was unable to rescue MSA prion infection in vitro, establishing that MSA α-synuclein prions are conformationally distinct from the misfolded α-synuclein in PD patients. This observation may have profound implications for developing treatments for neurodegenerative diseases.

KEYWORDS:

neurodegeneration; proteinopathy; strains; synucleinopathies; α-synuclein

PMID:
29279394
PMCID:
PMC5777081
DOI:
10.1073/pnas.1719369115
[Indexed for MEDLINE]
Free PMC Article

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