Viral alpha-synuclein knockdown prevents spreading synucleinopathy. Issue 4 (22nd October 2021)

• Record Type: Journal Article
• Authors: Menon, Sindhu; Kofoed, Rikke H; Nabbouh, Fadl; Xhima, Kristiana; Al-Fahoum, Yasmeen; Langman, Tammy; Mount, Howard T J; Shihabuddin, Lamya S; Sardi, S Pablo; Fraser, Paul E; Watts, Joel C; Aubert, Isabelle; Tandon, Anurag
• Is Part Of: Brain communications. Volume 3:Issue 4(2021)
• Publication Date: 2021-10-22
• Subjects: Parkinson's disease -- multiple system atrophy -- gene therapy -- gene silencing -- pathology; 616
• DOI: 10.1093/braincomms/fcab247
• Languages: English
• ISSNs: 2632-1297

Abstract

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. Abstract : 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: