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

Abstract

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 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.

Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication

“…Providing additional support for this hypothesis, the identification of distinct pathognomonic α-synuclein pathology along with unique symptoms in PD and MSA patients has contributed to the understanding that different conformations of misfolded α-synuclein are responsible for these diseases (5,(25)(26)(27)(28). The finding reported here that the E46K mutation, which gives rise to familial PD and DLB (11), obstructs the propagation of MSA prions in cultured cells provides remarkable evidence that MSA is caused by a unique α-synuclein prion strain.…”

“…Recent studies demonstrate that MSA is unequivocally caused by α-synuclein prions, which are misfolded proteins that undergo self-propagation and are capable of transmitting disease to transgenic (Tg) mice (3)(4)(5)(6). Using TgM83 +/− mice, which express human α-synuclein with the familial A53T mutation, both intracranial (3,5) and peripheral inoculation (6) of brain homogenate from a total of 17 MSA patients induced neurological disease in the animals. In addition, α-synuclein prions isolated from MSA patients propagated in cultured HEK cells that express mutant human α-synuclein*A53T fused to YFP (α-syn140*A53T−YFP) (4).…”

“…In addition, α-synuclein prions isolated from MSA patients propagated in cultured HEK cells that express mutant human α-synuclein*A53T fused to YFP (α-syn140*A53T−YFP) (4). While PD transmission studies have induced α-synuclein neuropathology (7)(8)(9), attempts to transmit disease to TgM83 +/− mice or to infect α-syn140*A53T−YFP cells have been unsuccessful (5), suggesting that distinct conformations of misfolded α-synuclein or α-synuclein prion strains may be responsible for these diseases.…”

Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells

“…Similar to tau, PrP Sc and multiple system atrophy (MSA) prions aggregate into fibrils that coalesce into amyloid plaques and glial cytoplasmic inclusions, respectively (37)(38)(39). Measuring the kinetics of PrP Sc and MSA propagation following intracerebral injection into Tg mice has been important in discerning the underlying biology of these prions.…”

Assemblages d’alpha-synucléine

“…1 Pathologies impliquant l'alpha-synucléine plusieurs équipes ont suggéré, dans des modèles expérimentaux in vivo, que la propagation de l'agrégation de l'alpha-synucléine se réaliserait selon un mécanisme qui ressemblerait à celui de la protéine prion, notamment dans un modèle transgénique murin de synucléi-nopathie développant une symptomatologie sévère [5][6][7]. Dans ce contexte, l'une des questions que se posent actuellement les chercheurs est la suivante : tout comme il existe des « souches » dans les maladies à prion, existe-t-il également des « souches » dans les pathologies associées à l'alpha-synucléine ?…”