Comparison of the in vivo induction and transmission of α-synuclein pathology by mutant α-synuclein fibril seeds in transgenic mice.

Parkinson's disease (PD) is one of many neurodegenerative diseases termed synucleinopathies, neuropathologically defined by inclusions containing aggregated alpha-synuclein (alpha S). alpha S gene (SNCA) mutations can directly cause autosomal dominant PD. In vitro studies demonstrated that SNCA missense mutations may either enhance or diminish alpha S aggregation but cross-seeding of mutant and wild-type alpha S proteins appear to reduce aggregation efficiency. Here, we extended these studies by assessing the effects of seeded alpha S aggregation in alpha S transgenic mice through intracerebral or peripheral injection of various mutant alpha S fibrils. We observed modestly decreased time to paralysis in mice transgenic for human A53T alpha S (line M83) intramuscularly injected with H50Q, G51D or A53E alpha S fibrils relative to wild-type alpha S fibrils. Conversely, E46K alpha S fibril seeding was significantly delayed and less efficient in the same experimental paradigm. However, the amount and distribution of alpha S inclusions in the central nervous system were similar for all alpha S fibril muscle injected mice that developed paralysis. Mice transgenic for human alpha S (line M20) injected in the hippocampus with wild-type, H50Q, G51D or A53E alpha S fibrils displayed induction of alpha S inclusion pathology that increased and spread over time. By comparison, induction of alpha S aggregation following the intrahippocampal injection of E46K alpha S fibrils in M20 mice was much less efficient. These findings show that H50Q, G51D or A53E can efficiently cross-seed and induce alpha S pathology in vivo. In contrast, E46K alpha S fibrils are intrinsically inefficient at seeding alpha S inclusion pathology. Consistent with previous in vitro studies, E46K alpha S polymers are likely distinct aggregated conformers that may represent a unique prion-like strain of alpha S.