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Updated: May 6, 2026
Bioluminescence Imaging of Neuroinflammation in Transgenic Mice After Peripheral Inoculation of Alpha-Synuclein Fibrils
Published on: April 13, 2017
Transmission of multiple system atrophy prions to transgenic mice
Joel C Watts1, Kurt Giles, Abby Oehler
1Institute 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.
Insights
Prion proteins cause synucleinopathies like Parkinson's disease. This study shows that alpha-synuclein aggregates from Multiple System Atrophy (MSA) brains are transmissible prions in mice.
Area of Science:
- Neuroscience
- Protein misfolding diseases
- Prion biology
Background:
- Prions are misfolded proteins that propagate themselves.
- Synucleinopathies, including Parkinson's disease and Multiple System Atrophy (MSA), are linked to alpha-synuclein.
- TgM83(+/+) mice develop neurological dysfunction due to mutant alpha-synuclein, while TgM83(+/-) mice do not.
Purpose of the Study:
- To investigate if alpha-synuclein aggregates in MSA brains are transmissible prions.
- To compare the transmission efficiency of MSA prions versus spontaneously occurring prions in Tg mice.
Main Methods:
- Inoculation of TgM83(+/-) mice with brain homogenates from confirmed MSA cases.
- Inoculation of TgM83(+/-) mice with brain homogenates from spontaneously ill TgM83(+/+) mice.
- Analysis of brain pathology in inoculated mice, including gliosis, microglial activation, and alpha-synuclein deposits.
Main Results:
- MSA brain homogenates transmitted neurological disease to TgM83(+/-) mice with a shorter incubation period (∼100 days) compared to TgM83(+/+) homogenates (∼210 days).
- Brains of MSA-inoculated mice showed characteristic prion disease pathology, including widespread phosphorylated alpha-synuclein deposits.
- These deposits exhibited prion-like properties: proteinase K sensitive, detergent insoluble, and formic acid extractable.
Conclusions:
- Alpha-synuclein aggregates in MSA patients are indeed transmissible prions.
- The MSA prion is a novel human pathogen that causes lethal neurological disease upon transmission to susceptible mice.
- This finding has significant implications for understanding the pathogenesis of synucleinopathies and the nature of human prion diseases.
