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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-09, Vol.112 (38), p.E5308-E5317
• Main Authors: Prusiner, Stanley B., Woerman, Amanda L., Mordes, Daniel A., Watts, Joel C., Rampersaud, Ryan, Berry, David B., Patel, Smita, Oehler, Abby, Lowe, Jennifer K., Kravitz, Stephanie N., Geschwind, Daniel H., Glidden, David V., Halliday, Glenda M., Middleton, Lefkos T., Gentleman, Steve M., Grinberg, Lea T., Giles, Kurt
• Format: Article
• Language: English
• Subjects: Aged; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Biological Sciences; Brain - pathology; Exons; Female; HEK293 Cells; Humans; Immunohistochemistry; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence; Middle Aged; Multiple System Atrophy - genetics; Multiple System Atrophy - metabolism; Neurodegenerative Diseases - metabolism; Parkinsonian Disorders - metabolism; Phosphorylation; PNAS Plus; Polymorphism, Single Nucleotide; Prions - metabolism; Ubiquinone - analogs & derivatives; Ubiquinone - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1514475112

Prions are proteins that adopt alternative conformations that become self-propagating; the PrPScprion 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.