title: Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation.
abstract: Hereditary spastic paraplegia, SPG31, is a rare neurological disorder caused by mutations in REEP1 gene encoding the microtubule-interacting protein, REEP1. The mechanism by which REEP1-dependent processes are linked with the disease is unclear. REEP1 regulates the morphology and trafficking of various organelles via interaction with the microtubules. In this study, we collected primary fibroblasts from SPG31 patients to investigate their mitochondrial morphology. We observed that the mitochondrial morphology in patient cells was highly tubular compared with control cells. We provide evidence that these morphological alterations are caused by the inhibition of mitochondrial fission protein, DRP1, due to the hyperphosphorylation of its serine 637 residue. This hyperphosphorylation is caused by impaired interactions between REEP1 and mitochondrial phosphatase PGAM5. Genetically or pharmacologically induced decrease of DRP1-S637 phosphorylation restores mitochondrial morphology in patient cells. Furthermore, ectopic expression of REEP1 carrying pathological mutations in primary neuronal culture targets REEP1 to the mitochondria. Mutated REEP1 proteins sequester mitochondria to the perinuclear region of the neurons and therefore, hamper mitochondrial transport along the axon. Considering the established role of mitochondrial distribution and morphology in neuronal health, our results support the involvement of a mitochondrial dysfunction in SPG31 pathology.
authors.affiliation: INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.|University of Bordeaux, 33077 Bordeaux, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Lavie
authors.affiliation: University of Bordeaux, 33077 Bordeaux, France.|INSERM U1215, NeuroCentre Magendie, 33077 Bordeaux, France.
authors.forename: Román
authors.initials: R
authors.lastname: Serrat
authors.affiliation: INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.|University of Bordeaux, 33077 Bordeaux, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Bellance
authors.affiliation: University of Bordeaux, 33077 Bordeaux, France.|INCIA, Université de Bordeaux, CNRS UMR5287, Bordeaux, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Courtand
authors.affiliation: University of Bordeaux, 33077 Bordeaux, France.|Plateforme Protéome, Centre de Génomique Fonctionnelle, F-33000 Bordeaux, France.
authors.forename: Jean-William
authors.initials: JW
authors.lastname: Dupuy
authors.affiliation: INSERM U1127, CNRS UMR 7225, UPMC Université Paris 06 UMR S1127, Sorbonne Université Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.|Ecole Pratique des Hautes Etudes, PSL Research University, 75014 Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Tesson
authors.affiliation: INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.|University of Bordeaux, 33077 Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupry
authors.affiliation: INSERM U1127, CNRS UMR 7225, UPMC Université Paris 06 UMR S1127, Sorbonne Université Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.|University of Bordeaux, 33077 Bordeaux, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: INSERM U1127, CNRS UMR 7225, UPMC Université Paris 06 UMR S1127, Sorbonne Université Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: INSERM U1127, CNRS UMR 7225, UPMC Université Paris 06 UMR S1127, Sorbonne Université Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.|Ecole Pratique des Hautes Etudes, PSL Research University, 75014 Paris, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.affiliation: INSERM U1127, CNRS UMR 7225, UPMC Université Paris 06 UMR S1127, Sorbonne Université Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Darios
authors.affiliation: INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.|University of Bordeaux, 33077 Bordeaux, France.
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
authors.affiliation: INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.|University of Bordeaux, 33077 Bordeaux, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: INSERM U1211, Laboratoire Maladies Rares: Génétique et Métabolisme. Hôpital Pellegrin, 33000 Bordeaux, France.|University of Bordeaux, 33077 Bordeaux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bénard
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000378:metabolism / Q000473:pathology
chemical_list: D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C495318:REEP1 protein, human; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins