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Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19555-60. doi: 10.1073/pnas.1318268110. Epub 2013 Nov 11.

Transmission of multiple system atrophy prions to transgenic mice.

Author information

1
Institute for Neurodegenerative Diseases, and Departments of Neurology and Pathology, University of California, San Francisco, CA 94143.

Abstract

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 α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83(+/-) mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-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 ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83(+/+) mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-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.

KEYWORDS:

bioluminescence imaging; neurodegeneration; proteinopathies; seeding

PMID:
24218576
PMCID:
PMC3845125
DOI:
10.1073/pnas.1318268110
[Indexed for MEDLINE]
Free PMC Article

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