Academic Journal
Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism
| العنوان: | Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism |
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| المؤلفون: | 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 |
| المساهمون: | Parkinson's UK |
| المصدر: | E5317 ; E5308 |
| بيانات النشر: | National Academy of Sciences |
| سنة النشر: | 2015 |
| المجموعة: | Imperial College London: Spiral |
| مصطلحات موضوعية: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, neurodegeneration, Parkinson's disease, synucleinopathies, strains, PROGRESSIVE SUPRANUCLEAR PALSY, GLIAL CYTOPLASMIC INCLUSIONS, CREUTZFELDT-JAKOB-DISEASE, TRANSGENIC MICE, LEWY BODIES, CONSENSUS STATEMENT, TRANSMISSION, MUTATIONS, SCRAPIE, Aged, Animals, Brain, Exons, Female, HEK293 Cells, Humans, Immunohistochemistry, Male, Mice, Transgenic, Microscopy, Fluorescence, Middle Aged |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0027-8424 |
| Relation: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; http://hdl.handle.net/10044/1/59346; https://dx.doi.org/10.1073/pnas.1514475112; J-1402 |
| DOI: | 10.1073/pnas.1514475112 |
| الاتاحة: | http://hdl.handle.net/10044/1/59346 https://doi.org/10.1073/pnas.1514475112 |
| Rights: | © 2015 The Author(s). Published by the National Academy of Sciences. |
| رقم الانضمام: | edsbas.233158E4 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00278424 |
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| DOI: | 10.1073/pnas.1514475112 |