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

  • Author(s): Prusiner, SB
  • Woerman, AL
  • Mordes, DA
  • Watts, JC
  • Rampersaud, R
  • Berry, DB
  • Patel, S
  • Oehler, A
  • Lowe, JK
  • Kravitz, SN
  • Geschwind, DH
  • Glidden, DV
  • Halliday, GM
  • Middleton, LT
  • Gentleman, SM
  • Grinberg, LT
  • Giles, K
  • et al.
Abstract

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.

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