Transmission of multiple system atrophy prions to transgenic mice.
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.
Institute for Neurodegenerative Diseases, and Departments of Neurology and Pathology, University of California, San Francisco, CA 94143.
Joel C
JC
Watts
Kurt
K
Giles
Abby
A
Oehler
Lefkos
L
Middleton
David T
DT
Dexter
Steve M
SM
Gentleman
Stephen J
SJ
DeArmond
Stanley B
SB
Prusiner
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018562:Disease Transmission, Infectious; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000378:metabolism* / Q000473:pathology; D011328:Prions / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D011328:Prions; D051844:alpha-Synuclein
bioluminescence imaging; neurodegeneration; proteinopathies; seeding