The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis

International Journal of Molecular Sciences

Safaa Saker¹  Thierry Larmonier¹  Pierre-François Pradat²  Vincent Meininger³  Francine Côté⁴  Laura Chartier⁵  Séverine Boillée⁵  François Salachas⁵  Mélanie Albert⁵  Delphine Roussel⁵  Danielle Seilhean⁵  Elisa Teyssou⁵  Dominique Langui⁵  Philippe Ravassard⁵  Stéphanie Millecamps⁵  Christian S. Lobsiger⁵  Ivan Nemazanyy⁶  Nirma D. Perera⁷  Bradley J. Turner⁷ 

[1] Banque d’ADN et de Cellules du Généthon, F-91000 Evry, France;Centre de Référence SLA Ile de France, Département de Neurologie, Hôpital de la Pitié-Salpêtrière, APHP, DMU Neuroscience, F-75013 Paris, France;Hôpital des Peupliers, Ramsay Générale de Santé, F-75013 Paris, France;Institut Cochin, INSERM U1016, CNRS UMR8104, Université de Paris, F-75014 Paris, France;Institut du Cerveau—Paris Brain Institute—ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Sorbonne Université, F-75013 Paris, France;Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR 3633, F-75015 Paris, France;The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia;

关键词: ALS;    genetics;    mutations;    alternative autophagy;    RAB9;    mitochondrial homeostasis;   

DOI  :  10.3390/ijms23105694

来源: DOAJ

【 摘 要 】

Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.

【 授权许可】

Unknown