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

Elisa Teyssou, Laura Chartier, Delphine Roussel, Nirma D. Perera, Ivan Nemazanyy, Dominique Langui, Mélanie Albert, Thierry Larmonier, Safaa Saker, François Salachas, Pierre-François Pradat, Vincent Meininger, Philippe Ravassard, Francine Côté, Christian S. Lobsiger, Séverine Boillée, Bradley J. Turner, Danielle Seilhean, Stéphanie Millecamps

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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.
Original languageEnglish
Article numbere5694
Pages (from-to)1-23
Number of pages23
JournalInternational Journal of Molecular Sciences
Issue number10
Early online date19 May 2022
Publication statusE-pub ahead of print - 19 May 2022


  • ALS
  • genetics
  • mutations
  • alternative autophagy
  • RAB9
  • mitochondrial homeostasis
  • post-mortem spinal cord
  • lymphoblasts
  • transgenic mice
  • NSC-34 cell line
  • Profilins - genetics - metabolism
  • rab GTP-Binding Proteins - metabolism
  • Humans
  • Homeostasis
  • Mitochondria - metabolism
  • Animals
  • Amyotrophic Lateral Sclerosis - metabolism
  • Mice
  • Autophagy - genetics
  • Mutation


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