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Intramuscular injection of ?-synuclein induces CNS ?-synuclein pathology and a rapid-onset motor phenotype in transgenic mice.

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Proc Natl Acad Sci U S A 2014 Jul; 111(29):10732-7

Authors: Amanda N Sacino, Mieu Brooks, Michael A Thomas, Alex B McKinney, Sooyeon Lee, Robert W Regenhardt, Nicholas H McGarvey, Jacob I Ayers, Lucia Notterpek, David R Borchelt, Todd E Golde, Benoit I Giasson

It has been hypothesized that ?-synuclein (?S) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that ?S pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of ?S can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) ?S transgenic (Tg) mouse models. Within 2-3 mo after IM injection in ?S homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS ?S inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed ?S inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing ?S CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of ?-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive ?S-induced neurodegeneration.

PMID: 25002524 [PubMed - as supplied by publisher]

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