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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2015,9,22]]},"abstract":"<jats:p>\n                    Prions are proteins that adopt alternative conformations that become self-propagating; the PrP\n                    <jats:sup>Sc<\/jats:sup>\n                    prion causes the rare human disorder Creutzfeldt\u2013Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the \u03b1-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 \u03b1-synuclein. To determine whether human \u03b1-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human \u03b1-synuclein fused to yellow fluorescent protein (\u03b1-syn140*A53T\u2013YFP) and TgM83\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice expressing \u03b1-synuclein (A53T). The TgM83\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83\n                    <jats:sup>+\/+<\/jats:sup>\n                    mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice after incubation periods of \u223c120 d, which was accompanied by deposition of \u03b1-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of \u03b1-syn*A53T\u2013YFP in cultured cells, whereas none of six Parkinson\u2019s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of \u03b1-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83\n                    <jats:sup>+\/+<\/jats:sup>\n                    mice. Remarkably, \u03b1-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1514475112","type":"journal-article","created":{"date-parts":[[2015,8,31]],"date-time":"2015-08-31T22:19:53Z","timestamp":1441059593000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":673,"title":["Evidence for \u03b1-synuclein prions causing multiple system atrophy in humans with parkinsonism"],"prefix":"10.1073","volume":"112","author":[{"given":"Stanley B.","family":"Prusiner","sequence":"first","affiliation":[{"name":"Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;"},{"name":"Department of Neurology, University of California, San Francisco, CA 94143;"},{"name":"Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Woerman","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel A.","family":"Mordes","sequence":"additional","affiliation":[{"name":"C. 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Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel C.","family":"Watts","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;"},{"name":"Department of Neurology, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Rampersaud","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Berry","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita","family":"Patel","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abby","family":"Oehler","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Lowe","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Center for Autism Research and Treatment, and Department of Neurology, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie N.","family":"Kravitz","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Center for Autism Research and Treatment, and Department of Neurology, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H.","family":"Geschwind","sequence":"additional","affiliation":[{"name":"Center for Neurobehavioral Genetics, Center for Autism Research and Treatment, and Department of Neurology, University of California, Los Angeles, CA 90095;"},{"name":"Department of Human Genetics, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David V.","family":"Glidden","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glenda M.","family":"Halliday","sequence":"additional","affiliation":[{"name":"School of Medical Science, Faculty of Medicine, University of New South Wales, and Neuroscience Research Australia, Randwick, NSW 2031, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lefkos T.","family":"Middleton","sequence":"additional","affiliation":[{"name":"Ageing Research Unit, School of Public Health, Imperial College London, London SW7 2AZ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve M.","family":"Gentleman","sequence":"additional","affiliation":[{"name":"Centre for Neuroinflammation and Neurodegeneration, Department of Medicine, Imperial College London, London SW7 2AZ, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea T.","family":"Grinberg","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, San Francisco, CA 94143;"},{"name":"Memory and Aging Center, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Giles","sequence":"additional","affiliation":[{"name":"Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143;"},{"name":"Department of Neurology, University of California, San Francisco, CA 94143;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2015,8,31]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/209794a0"},{"key":"e_1_3_4_2_2","first-page":"343","article-title":"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\u2019s disease","volume":"36","author":"Gibbs CJ","year":"1982","unstructured":"Jr CJ Gibbs , DC Gajdusek , 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\u2019s disease. 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