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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Abstract

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 number5694
Pages (from-to)5694
Number of pages1
JournalInternational Journal of Molecular Sciences
Volume23
Issue number10
Early online date19 May 2022
DOIs
Publication statusPublished (in print/issue) - 19 May 2022

Bibliographical note

Funding Information:
This research was funded by the Association pour la Recherche sur la Sclérose latérale amyotrophique et autres maladies du motoneurone (ARSla, France, contract R11010DD, to PFP, contracts R17050DD, S.3200.ARSLA.1, to SM), the Association Française contre les Myopathies (AFM, France, #19466, to SM), the Aide à la Recherche des Maladies du Cerveau association (ARMC, France, contract R16009DD, to SM) and the Fédération pour la Recherche sur le Cerveau (FRC, France, contract AO‐FRC 2009 #33536, to SM). Lentiviral transgenesis technology was funded by GlaxoSmithKline research support (contract CT110725). A Stafford Fox Medical Research Foundation Grant supported BJT. The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant. ET was supported by a PhD Fellowship from AFM (#18145) and benefited from a student exchange program between ICM (France) and the Florey Institute of Neuroscience and Mental Health (Australia).We acknowledge the patients and their family. We thank the Généthon cell and DNA bank (Evry, France) and the ICM DNA and cell bank (Paris, France) for patient DNA and lymphoblasts. We thank the UMS 28 (for lentiviral transgenesis) and the following ICM core facilities (Paris, France) for equipment access: CELIS (cell culture), iVector (lentiviral production), PHENO‐ICMice (mouse phenotyping) and HISTOMICS (tissue slides) which received funding from the program “Investissements d’avenir” ANR‐10‐IAIHU‐06.

Funding Information:
Acknowledgments: We acknowledge the patients and their family. We thank the Généthon cell and DNA bank (Evry, France) and the ICM DNA and cell bank (Paris, France) for patient DNA and lymphoblasts. We thank the UMS 28 (for lentiviral transgenesis) and the following ICM core facili‐ ties (Paris, France) for equipment access: CELIS (cell culture), iVector (lentiviral production), PHENO‐ICMice (mouse phenotyping) and HISTOMICS (tissue slides) which received funding from the program “Investissements d’avenir” ANR‐10‐IAIHU‐06.

Funding Information:
Funding: This research was funded by the Association pour la Recherche sur la Sclérose latérale amyotrophique et autres maladies du motoneurone (ARSla, France, contract R11010DD, to PFP, contracts R17050DD, S.3200.ARSLA.1, to SM), the Association Française contre les Myopathies (AFM, France, #19466, to SM), the Aide à la Recherche des Maladies du Cerveau association (ARMC, France, contract R16009DD, to SM) and the Fédération pour la Recherche sur le Cerveau (FRC, France, contract AO‐FRC 2009 #33536, to SM). Lentiviral transgenesis technology was funded by GlaxoSmithKline research support (contract CT110725). A Stafford Fox Medical Research Founda‐ tion Grant supported BJT. The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Opera‐ tional Infrastructure Support Grant. ET was supported by a PhD Fellowship from AFM (#18145) and benefited from a student exchange program between ICM (France) and the Florey Institute of Neuroscience and Mental Health (Australia).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • 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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