期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 48, 页码 19555-19560出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1318268110
关键词
neurodegeneration; bioluminescence imaging; seeding; proteinopathies
资金
- National Institutes of Health [AG002132, AG010770, AG031220]
- National Institute on Aging K99 [AG042453]
- Parkinson's United Kingdom Tissue Bank at Imperial College
- Parkinson's United Kingdom, a charity registered in England and Wales [948776]
- Parkinson's United Kingdom, a charity registered in England and Scotland [SC037554]
- Leverhulme Trust
- Parkinson's UK [G-0909] Funding Source: researchfish
Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson's disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83(+/+) mice homozygous for a mutant A53T alpha-synuclein transgene begin developing CNS dysfunction spontaneously at similar to 10 mo of age, uninoculated TgM83(+/-) mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain alpha-synuclein prions, we inoculated the TgM83(+/-) mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83(+/-) mice developed progressive signs of neurologic disease with an incubation period of similar to 100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83(+/+) mice developed neurologic dysfunction in similar to 210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated alpha-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that alpha-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.
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