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

Proc Natl Acad Sci U S A 2015 Sep 31;112(38):E5308-17. Epub 2015 Aug 31.

Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143; Department of Neurology, University of California, San Francisco, CA 94143;

Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) 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.

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1514475112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586853PMC
September 2015
28 Reads

Publication Analysis

Top Keywords

tgm83+/- mice
12
system atrophy
8
human prion
8
α-synuclein
8
human α-synuclein
8
tgm83+/+ mice
8
multiple system
8
α-synuclein prions
8
msa caused
8
prions causing
8
human
7
msa
6
prions
5
mice
5
α-synuclein neuronal
4
brain homogenates
4
deposition α-synuclein
4
human brain
4
examined human
4
cultured human
4

References

(Supplied by CrossRef)
An update on long-term in vivo and in vitro studies designed to identify a virus as the cause of amyotrophic lateral sclerosis, parkinsonism dementia, and Parkinson’s disease
Gibbs et al.
Adv Neurol 1982

Similar Publications