Viral alpha-synuclein knockdown prevents spreading synucleinopathy
Sindhu Menon, Rikke Hahn Kofoed, Fadl Nabbouh, Kristiana Xhima, Yasmeen Al-Fahoum, Tammy Langman, Howard T.J. Mount, Lamya S. Shihabuddin, S. Pablo Sardi, Paul E. Fraser, Joel C. Watts, Isabelle Aubert, Anurag Tandon
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.