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Proc Natl Acad Sci U S A. 2015 Sep 22;112(38):E5308-17. doi: 10.1073/pnas.1514475112. Epub 2015 Aug 31.

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

Author information

  • 1Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143; Department of Neurology, University of California, San Francisco, CA 94143; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143; stanley@ind.ucsf.edu.
  • 2Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;
  • 3C. S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114;
  • 4Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143; Department of Neurology, University of California, San Francisco, CA 94143;
  • 5Department of Pathology, University of California, San Francisco, CA 94143;
  • 6Center for Neurobehavioral Genetics, Center for Autism Research and Treatment, and Department of Neurology, University of California, Los Angeles, CA 90095;
  • 7Center for Neurobehavioral Genetics, Center for Autism Research and Treatment, and Department of Neurology, University of California, Los Angeles, CA 90095; Department of Human Genetics, University of California, Los Angeles, CA 90095;
  • 8Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143;
  • 9School of Medical Science, Faculty of Medicine, University of New South Wales, and Neuroscience Research Australia, Randwick, NSW 2031, Australia;
  • 10Ageing Research Unit, School of Public Health, Imperial College London, London SW7 2AZ, United Kingdom;
  • 11Centre for Neuroinflammation and Neurodegeneration, Department of Medicine, Imperial College London, London SW7 2AZ, United Kingdom;
  • 12Department of Neurology, University of California, San Francisco, CA 94143; Memory and Aging Center, University of California, San Francisco, CA 94143.

Abstract

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.

KEYWORDS:

Parkinson's disease; neurodegeneration; strains; synucleinopathies

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PMID:
26324905
[PubMed - indexed for MEDLINE]
PMCID:
PMC4586853
Free PMC Article
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