Viral alpha-synuclein knockdown prevents spreading synucleinopathy

Abstract

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