4 years ago

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

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

Publisher URL: http://doi.org/10.1093/hmg/ddx371

DOI: 10.1093/hmg/ddx371

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