Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism.
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.
Institute 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.
Stanley B
SB
Prusiner
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;
Amanda L
AL
Woerman
C. S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114;
Daniel A
DA
Mordes
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143; Department of Neurology, University of California, San Francisco, CA 94143;
Joel C
JC
Watts
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;
Ryan
R
Rampersaud
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;
David B
DB
Berry
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;
Smita
S
Patel
Department of Pathology, University of California, San Francisco, CA 94143;
Abby
A
Oehler
Center for Neurobehavioral Genetics, Center for Autism Research and Treatment, and Department of Neurology, University of California, Los Angeles, CA 90095;
Jennifer K
JK
Lowe
Center for Neurobehavioral Genetics, Center for Autism Research and Treatment, and Department of Neurology, University of California, Los Angeles, CA 90095;
Stephanie N
SN
Kravitz
Center 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;
Daniel H
DH
Geschwind
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143;
David V
DV
Glidden
School of Medical Science, Faculty of Medicine, University of New South Wales, and Neuroscience Research Australia, Randwick, NSW 2031, Australia;
Glenda M
GM
Halliday
Ageing Research Unit, School of Public Health, Imperial College London, London SW7 2AZ, United Kingdom;
Lefkos T
LT
Middleton
Centre for Neuroinflammation and Neurodegeneration, Department of Medicine, Imperial College London, London SW7 2AZ, United Kingdom;
Steve M
SM
Gentleman
Department of Neurology, University of California, San Francisco, CA 94143; Memory and Aging Center, University of California, San Francisco, CA 94143.
Lea T
LT
Grinberg
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143; Department of Neurology, University of California, San Francisco, CA 94143;
Kurt
K
Giles
D000368:Aged; D000818:Animals; D001921:Brain / Q000473:pathology; D005091:Exons; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000378:metabolism*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D011328:Prions / Q000378:metabolism*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D011328:Prions; C497604:SNCA protein, human; D051844:alpha-Synuclein; D014451:Ubiquinone; C024989:coenzyme Q10
Parkinson's disease; neurodegeneration; strains; synucleinopathies