Viral alpha-synuclein knockdown prevents spreading synucleinopathy

Abstract The accumulation of aggregated alpha-synuclein (α-syn) in Parkinson's disease, dementia with Lewy bodies and multiple system atrophy is thought to involve a common prion-like mechanism, whereby misfolded α-syn provides a conformational template for further accumulation of pathological α-syn. We tested whether silencing α-syn gene expression could reduce native non-aggregated α-syn substrate and thereby disrupt the propagation of pathological α-syn initiated by seeding with synucleinopathy-affected mouse brain homogenates. Unilateral intracerebral injections of adeno-associated virus serotype-1 encoding microRNA targeting the α-syn gene reduced the extent and severity of both the α-syn pathology and motor deficits. Importantly, a moderate 50% reduction in α-syn was sufficient to prevent the spread of α-syn pathology to distal brain regions. Our study combines behavioural, immunohistochemical and biochemical data that strongly support α-syn knockdown gene therapy for synucleinopathies. Menon et al. report that AAV1-mediated expression of microRNA targeting alpha-synuclein gene expression reduced both motor deficits and pathology in mice that were initiated by an injection of synucleinopathy-affected brain homogenates. Partial suppression of alpha-synuclein was sufficient to prevent pathology spreading into distal brain regions with normal alpha-synuclein levels. Graphical Abstract Graphical Abstract