The process of Lewy body formation, rather than simply α-synuclein fibrillization, is one of the major drivers of neurodegeneration
| Autor: | Anne-Laure Mahul-Mellier, Niran Maharjan, Marie Croisier, Laura Weerens, Johannes Burtscher, Marion Leleu, Graham Knott, Fabien Kuttler, Hilal A. Lashuel |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Autophagosome Parkinson's disease Mitochondrion 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Process (anatomy) Neurons Multidisciplinary α‐synuclein Lewy body Chemistry Neurodegeneration Autophagosomes aggregation Neurodegenerative Diseases Parkinson Disease Biological Sciences medicine.disease Endolysosome Mitochondria Cell biology 030104 developmental biology alpha-Synuclein Parkinson’s disease Lewy Bodies Lysosomes Transcriptome seeding 030217 neurology & neurosurgery Biogenesis Neuroscience |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1913904117 |
| Popis: | Significance Although converging evidence point to α-synuclein aggregation and Lewy body (LB) formation as central events in Parkinson’s disease, the molecular mechanisms that regulate these processes and their role in disease pathogenesis remain elusive. Herein, we describe a neuronal model that reproduces the key events leading to the formation of inclusions that recapitulate the biochemical, structural, and organizational features of bona fide LBs. This model allowed us to dissect the molecular events associated with the different stages of LB formation and how they contribute to neuronal dysfunctions and degeneration, thus providing a powerful platform for evaluating therapeutics targeting α-synuclein aggregation and LB formation and to identify and validate therapeutic targets for the treatment of Parkinson’s disease. Parkinson’s disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD, the processes that govern α-syn fibrillization and LB formation remain poorly understood. In this work, we sought to dissect the spatiotemporal events involved in the biogenesis of the LBs at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we further developed a seeding-based model of α-syn fibrillization to generate a neuronal model that reproduces the key events leading to LB formation, including seeding, fibrillization, and the formation of inclusions that recapitulate many of the biochemical, structural, and organizational features of bona fide LBs. Using an integrative omics, biochemical and imaging approach, we dissected the molecular events associated with the different stages of LB formation and their contribution to neuronal dysfunction and degeneration. In addition, we demonstrate that LB formation involves a complex interplay between α-syn fibrillization, posttranslational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria, the autophagosome, and endolysosome. Finally, we show that the process of LB formation, rather than simply fibril formation, is one of the major drivers of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, and synaptic dysfunctions. We believe that this model represents a powerful platform to further investigate the mechanisms of LB formation and clearance and to screen and evaluate therapeutics targeting α-syn aggregation and LB formation. |
| Databáze: | OpenAIRE |
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