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 PrPSc 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 alpha-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 alpha-synuclein. To determine whether human alpha-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human alpha-synuclein fused to yellow fluorescent protein (alpha-syn140*A53T-YFP) and TgM83(+/-) mice expressing alpha-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 similar to 120 d, which was accompanied by deposition of alpha-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of alpha-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 alpha-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, alpha-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.