| First Author | Rutherford NJ | Year | 2017 |
| Journal | Hum Mol Genet | Volume | 26 |
| Issue | 24 | Pages | 4906-4915 |
| PubMed ID | 29036344 | Mgi Jnum | J:252725 |
| Mgi Id | MGI:6094289 | Doi | 10.1093/hmg/ddx371 |
| Citation | Rutherford NJ, et al. (2017) Comparison of the in vivo induction and transmission of alpha-synuclein pathology by mutant alpha-synuclein fibril seeds in transgenic mice. Hum Mol Genet 26(24):4906-4915 |
| abstractText | Parkinson's disease (PD) is one of many neurodegenerative diseases termed synucleinopathies, neuropathologically defined by inclusions containing aggregated alpha-synuclein (alphaS). alphaS gene (SNCA) mutations can directly cause autosomal dominant PD. In vitro studies demonstrated that SNCA missense mutations may either enhance or diminish alphaS aggregation but cross-seeding of mutant and wild-type alphaS proteins appear to reduce aggregation efficiency. Here, we extended these studies by assessing the effects of seeded alphaS aggregation in alphaS transgenic mice through intracerebral or peripheral injection of various mutant alphaS fibrils. We observed modestly decreased time to paralysis in mice transgenic for human A53T alphaS (line M83) intramuscularly injected with H50Q, G51D or A53E alphaS fibrils relative to wild-type alphaS fibrils. Conversely, E46K alphaS fibril seeding was significantly delayed and less efficient in the same experimental paradigm. However, the amount and distribution of alphaS inclusions in the central nervous system were similar for all alphaS fibril muscle injected mice that developed paralysis. Mice transgenic for human alphaS (line M20) injected in the hippocampus with wild-type, H50Q, G51D or A53E alphaS fibrils displayed induction of alphaS inclusion pathology that increased and spread over time. By comparison, induction of alphaS aggregation following the intrahippocampal injection of E46K alphaS fibrils in M20 mice was much less efficient. These findings show that H50Q, G51D or A53E can efficiently cross-seed and induce alphaS pathology in vivo. In contrast, E46K alphaS fibrils are intrinsically inefficient at seeding alphaS inclusion pathology. Consistent with previous in vitro studies, E46K alphaS polymers are likely distinct aggregated conformers that may represent a unique prion-like strain of alphaS. |
