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

ABSTRACT: Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) 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 ?-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 ?-synuclein. To determine whether human ?-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human ?-synuclein fused to yellow fluorescent protein (?-syn140*A53T-YFP) and TgM83(+/-) mice expressing ?-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 ?-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of ?-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 ?-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, ?-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

SUBMITTER: Prusiner SB

PROVIDER: S-EPMC4586853 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Prusiner Stanley B SB Woerman Amanda L AL Mordes Daniel A DA Watts Joel C JC Rampersaud Ryan R Berry David B DB Patel Smita S Oehler Abby A Lowe Jennifer K JK Kravitz Stephanie N SN Geschwind Daniel H DH Glidden David V DV Halliday Glenda M GM Middleton Lefkos T LT Gentleman Steve M SM Grinberg Lea T LT Giles Kurt K

Proceedings of the National Academy of Sciences of the United States of America 20150831 38

Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) 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 ...[more]

PMID: 26324905

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Project description:Both Parkinson's disease (PD) and multiple system atrophy (MSA) have associated sleep disorders related to the underlying neurodegenerative pathology. Clinically, MSA with predominant parkinsonism (MSA-P) resembles PD in the manifestation of prominent parkinsonism. Whether the amount of rapid eye movement (REM) sleep without atonia could be a potential marker for differentiating MSA-P from PD has not been thoroughly investigated. This study aimed to examine whether sleep parameters could provide a method for differentiating MSA-P from PD.This study comprised 24 MSA-P patients and 30 PD patients, and they were of similar age, gender, and REM sleep behavior disorder (RBD) prevalence. All patients underwent clinical evaluation and one night of video-polysomnography recording. The tonic and phasic chin electromyogram (EMG) activity was manually quantified during REM sleep of each patient. We divided both groups in terms of whether they had RBD to make subgroup analysis.No significant difference between MSA-P group and PD group had been found in clinical characteristics and sleep architecture. However, MSA-P patients had higher apnea-hypopnea index (AHI; 1.15 [0.00, 8.73]/h vs. 0.00 [0.00, 0.55]/h, P = 0.024) and higher tonic chin EMG density (34.02 [18.48, 57.18]% vs. 8.40 [3.11, 13.06]%, P < 0.001) as compared to PD patients. Subgroup analysis found that tonic EMG density in MSA + RBD subgroup was higher than that in PD + RBD subgroup (55.04 [26.81, 69.62]% vs. 11.40 [8.51, 20.41]%, P < 0.001). Furthermore, no evidence of any difference in tonic EMG density emerged between PD + RBD and MSA - RBD subgroups (P > 0.05). Both disease duration (P = 0.056) and AHI (P = 0.051) showed no significant differences during subgroup analysis although there was a trend toward longer disease duration in PD + RBD subgroup and higher AHI in MSA - RBD subgroup. Stepwise multiple linear regression analysis identified the presence of MSA-P (? = 0.552, P < 0.001) and RBD (? = 0.433, P < 0.001) as predictors of higher tonic EMG density.Tonic chin EMG density could be a potential marker for differentiating MSA-P from PD.

Dataset Information

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

Publications

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

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