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Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism

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Title: Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism
Authors: Prusiner, SB
Woerman, AL
Mordes, DA
Watts, JC
Rampersaud, R
Berry, DB
Patel, S
Oehler, A
Lowe, JK
Kravitz, SN
Geschwind, DH
Glidden, DV
Halliday, GM
Middleton, LT
Gentleman, SM
Grinberg, LT
Giles, K
Item Type: Journal Article
Abstract: Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/− mice expressing α-synuclein (A53T). The TgM83+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.
Issue Date: 22-Sep-2015
Date of Acceptance: 22-Jul-2015
URI: http://hdl.handle.net/10044/1/59346
DOI: https://dx.doi.org/10.1073/pnas.1514475112
ISSN: 0027-8424
Publisher: National Academy of Sciences
Start Page: E5308
End Page: E5317
Journal / Book Title: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume: 112
Issue: 38
Copyright Statement: © 2015 The Author(s). Published by the National Academy of Sciences.
Sponsor/Funder: Parkinson's UK
Funder's Grant Number: J-1402
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
neurodegeneration
Parkinson's disease
synucleinopathies
strains
PROGRESSIVE SUPRANUCLEAR PALSY
GLIAL CYTOPLASMIC INCLUSIONS
CREUTZFELDT-JAKOB-DISEASE
TRANSGENIC MICE
LEWY BODIES
CONSENSUS STATEMENT
TRANSMISSION
MUTATIONS
SCRAPIE
NEURODEGENERATION
Aged
Animals
Brain
Exons
Female
HEK293 Cells
Humans
Immunohistochemistry
Male
Mice
Mice, Transgenic
Microscopy, Fluorescence
Middle Aged
Multiple System Atrophy
Neurodegenerative Diseases
Parkinsonian Disorders
Phosphorylation
Polymorphism, Single Nucleotide
Prions
Ubiquinone
alpha-Synuclein
MD Multidisciplinary
Publication Status: Published
Open Access location: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586853/pdf/pnas.201514475.pdf
Online Publication Date: 2015-08-31
Appears in Collections:Department of Medicine
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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