Viral alpha-synuclein knockdown prevents spreading synucleinopathy

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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.
Funding Information
  • Canadian Institutes of Health Research (PJT148736, FRN166184, FRN168906, PJT173497)
  • Canada Research Chairs Program to IA and JCW
  • Canadian Alzheimer Society Research Program Postdoctoral Fellowship (#19-10)
  • Carlsberg Foundation Internationalisation Stipend (#CF20-0379)
  • Queen Elizabeth II Graduate Scholarship in Science and Technology program
  • Frederick Banting and Charles Best Canada Graduate Scholarship GSD (152271)

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