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Résumés / Abstracts

Abstract ID
Poster TH1-02

Optogenetic-mediated spatiotemporal control of α-synuclein aggregation mimics authentic Lewy body formation and triggers neurodegeneration

MORGAN BERARD1,2, Razan Sheta1,2, Sarah Malvaut3,4, Raquel Rodriguez-Aller1,2,3, Maxime Teixeira1,2, Roxanne Turmel1,2, Melanie Alpaugh1,4, Marilyn Dubois1,2, Manel Dahmene1,2, Charleen Sales3,4, Jérôme Lamontagne-Proulx1,5, Marie-Kim St-Pierre1,2, Omid Tavassoly6, Wen Luo6, Raza Qazi7, Jae-Woong Jeong7,8, Thomas M. Durcan6, Luc Vallières1,2, Marie-Eve Tremblay1,2,9, Denis Soulet1,5, Martin Lévesque3,4, Francesca Cicchetti1,4, Edward A. Fon6, Armen Saghatelyan3,4, Abid Oueslati1,2

1CHU de Quebec Research Center, Axe Neurosciences. 2Department of Molecular Medicine, Faculty of medicine, Université Laval, Quebec City, Canada.3CERVO Brain Research Centre. 4Department of Psychiatry and Neurosciences, Faculty of medicine, Université Laval, Quebec City. 5Faculty of Pharmacy, Université Laval, Quebec City, Canada. 6McGill Parkinson Program and Neurodegenerative Diseases Group, Montreal Neurological Institute, McGill University, Montreal, Canada. 7Department of Electrical, Computer, and Energy Engineering, University of Colorado, Boulder, CO 80309, USA. 8School of Electrical Engineering Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea. 8Division of Medical Sciences, University of Victoria, Victoria, Canada.

α-synuclein (α-syn) aggregation into insoluble deposits, referred to as Lewy bodies (LBs) is the paramount pathological hallmark of Parkinson’s disease (PD) and related α-synucleinopathies. However, how these aggregates affect neuronal homeostasis leading to neurodegeneration remains elusive. This gap in knowledge is mainly due to the lack of proper cellular and animal models to undertake such investigations.
We have addressed this limitation by developing a light-inducible protein aggregation system (LIPA). This application is based on the use of a mutant form of the Arabidopsis thaliana photoreceptor cryptochrome 2 (CRY2), which when stimulated with blue light, mutant CRY2 undergoes rapid, reversible and robust protein clustering or aggregation. The use of this application allows for real-time induction of α-syn inclusions formation with remarkable spatial and temporal resolution in both cell culture and in vivo paradigms.
We used a gene therapy approach, based on the use of adeno-associated virus (AAV), to overexpress our LIPA system directly into the brains of naive mice. For the delivery of the blue light necessary for the induction of the aggregation and propagation of α-syn, we used implantable micro-devices developed by Amuza Inc.
We report on the development of a light-inducible protein aggregation (LIPA) system that enables real-time induction of α-syn inclusion formation with remarkable spatial and temporal resolution in living cells. We demonstrate that LIPA-α-syn inclusions faithfully mimic key biochemical and ultrastructural features, as well as the seeding capacity of authentic LBs. In vivo, LIPA-α-syn aggregates compromised the nigrostriatal transmission, induced dopaminergic neuronal loss and PD-like behavioral impairment.
Our system provides a novel, dependable and invaluable tool to generate, visualize and dissect the role of protein aggregates in PD and possibly other neurodegenerative disorders.