| First Author | Sacino AN | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 29 | Pages | 10732-7 |
| PubMed ID | 25002524 | Mgi Jnum | J:212256 |
| Mgi Id | MGI:5578400 | Doi | 10.1073/pnas.1321785111 |
| Citation | Sacino AN, et al. (2014) Intramuscular injection of alpha-synuclein induces CNS alpha-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci U S A 111(29):10732-7 |
| abstractText | It has been hypothesized that alpha-synuclein (alphaS) 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 alphaS 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 alphaS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) alphaS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in alphaS 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 alphaS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed alphaS 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 alphaS 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 alpha-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive alphaS-induced neurodegeneration. |
