Viral alpha-synuclein knockdown prevents spreading synucleinopathy

Author:

Menon Sindhu1,Kofoed Rikke H2,Nabbouh Fadl1,Xhima Kristiana23ORCID,Al-Fahoum Yasmeen1,Langman Tammy1,Mount Howard T J145,Shihabuddin Lamya S6,Sardi S Pablo6,Fraser Paul E17,Watts Joel C18,Aubert Isabelle23,Tandon Anurag19ORCID

Affiliation:

1. Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON M5T 0S8, Canada

2. Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada

3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada

4. Department of Psychiatry, University of Toronto, Toronto, ON M5S 1A1, Canada

5. Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada

6. Sanofi, Framingham, MA 01701, USA

7. Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A1, Canada

8. Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A1, Canada

9. Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada

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.

Funder

Canadian Institutes of Health Research

Canada Research Chairs Program to IA and JCW

Canadian Alzheimer Society Research Program Postdoctoral Fellowship

Carlsberg Foundation Internationalisation Stipend

Queen Elizabeth II Graduate Scholarship in Science and Technology Program

Frederick Banting and Charles Best Canada Graduate Scholarship GSD

Publisher

Oxford University Press (OUP)

Subject

General Earth and Planetary Sciences,General Environmental Science

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