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The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies

Anne-Laure Mahul-Mellier, Johannes Burtscher, Niran Maharjan, Laura Weerens, Marie Croisier, Fabien Kuttler, Marion Leleu, Graham Knott, Hilal A. Lashuel
doi: https://doi.org/10.1101/751891
Anne-Laure Mahul-Mellier
1Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
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Johannes Burtscher
1Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
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Niran Maharjan
1Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
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Laura Weerens
1Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
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Marie Croisier
2BioEM Core Facility and Technology Platform, EPFL, Lausanne 1015, Switzerland
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Fabien Kuttler
3BiomolecularScreening Core Facility and Technology Platform, EPFL, Lausanne 1015, Switzerland
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Marion Leleu
4Gene expression Core Facility and Technology Platform, EPFL, Lausanne 1015, Switzerland
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Graham Knott
2BioEM Core Facility and Technology Platform, EPFL, Lausanne 1015, Switzerland
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Hilal A. Lashuel
1Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
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  • For correspondence: hilal.lashuel@epfl.ch
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Abstract

Parkinson’s disease (PD) is characterized by the accumulation of misfolded alpha-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LB). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD and synucleinopathies, the processes that govern α-syn fibrillization and LB formation in the brain remain poorly understood. In this work, we sought to reverse engineer LBs and dissect the spatiotemporal events involved in their biogenesis at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we took advantage of a seeding-based model of α-syn fibril formation in primary neurons and further developed this model to generate the first neuronal model that reproduces the key events leading to LB formation; including seeding, fibrillization, and the formation of LB-like inclusions that recapitulate many of the biochemical, structural, and organizational features of LBs found in post-mortem human PD brain tissues. Next, we applied an integrative approach combining confocal and correlative light-electron microscopy (CLEM) imaging methods with biochemical profiling of α-syn species and temporal proteomic and transcriptomic analyses to dissect the molecular events associated with LB formation and maturation and to elucidate their contributions to neuronal dysfunctions and neurodegeneration in PD and synucleinopathies. The results from these studies demonstrate that LB formation involves a complex interplay between α-syn fibrillization, post-translational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria and the autophagosome and endolysosome. Furthermore, we demonstrate that the process of LB formation and maturation, rather than simply fibril formation, is the major driver of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, as well as synaptic dysfunctions. Having a neuronal model that allows for unlinking of the key processes involved in LB formation is crucial for elucidating the molecular and cellular determinants of each process and their contributions to neuronal dysfunction and degeneration in PD and synucleinopathies. Such a model is essential to efforts to identify and investigate the mode of action and toxicity of drug candidates targeting α-syn aggregation and LB formation.

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Posted September 02, 2019.
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The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies
Anne-Laure Mahul-Mellier, Johannes Burtscher, Niran Maharjan, Laura Weerens, Marie Croisier, Fabien Kuttler, Marion Leleu, Graham Knott, Hilal A. Lashuel
bioRxiv 751891; doi: https://doi.org/10.1101/751891
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The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is the major driver of neurodegeneration in synucleinopathies
Anne-Laure Mahul-Mellier, Johannes Burtscher, Niran Maharjan, Laura Weerens, Marie Croisier, Fabien Kuttler, Marion Leleu, Graham Knott, Hilal A. Lashuel
bioRxiv 751891; doi: https://doi.org/10.1101/751891

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