Transmission of multiple system atrophy prions to transgenic mice.

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 ?-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 ?-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 ?-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that ?-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.

SUBMITTER: Watts JC 

PROVIDER: S-EPMC3845125 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature