title: Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD.
abstract: Mutations in SQSTM1, encoding for the protein SQSTM1/p62, have been recently reported in 1-3.5% of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Inclusions positive for SQSTM1/p62 have been detected in patients with neurodegenerative disorders, including ALS/FTLD. In order to investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS/FTLD, we developed a zebrafish model. Knock-down of the sqstm1 zebrafish ortholog, as well as impairment of its splicing, led to a specific phenotype, consisting of behavioral and axonal anomalies. Here, we report swimming deficits associated with shorter motor neuronal axons that could be rescued by the overexpression of wild-type human SQSTM1. Interestingly, no rescue of the loss-of-function phenotype was observed when overexpressing human SQSTM1 constructs carrying ALS/FTLD-related mutations. Consistent with its role in autophagy regulation, we found increased mTOR levels upon knock-down of sqstm1. Furthermore, treatment of zebrafish embryos with rapamycin, a known inhibitor of the mTOR pathway, yielded an amelioration of the locomotor phenotype in the sqstm1 knock-down model. Our results suggest that loss-of-function of SQSTM1 causes phenotypic features characterized by locomotor deficits and motor neuron axonal defects that are associated with a misregulation of autophagic processes.
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris, F-75013 Paris, France.
authors.forename: Serena
authors.initials: S
authors.lastname: Lattante
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris, F-75013 Paris, France.
authors.forename: Hortense
authors.initials: H
authors.lastname: de Calbiac
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris, F-75013 Paris, France, AP-HP, Hôpital de la Salpêtrière, Centre de Référence Démences Rares, F-75013, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris, F-75013 Paris, France, AP-HP, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, F-75013, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris, F-75013 Paris, France, sorana.ciura@icm-institute.org edor.kabashi@icm-institute.org.
authors.forename: Sorana
authors.initials: S
authors.lastname: Ciura
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris, F-75013 Paris, France, sorana.ciura@icm-institute.org edor.kabashi@icm-institute.org.
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D057174:Frontotemporal Lobar Degeneration / Q000188:drug therapy / Q000235:genetics*; D055785:Gene Knockdown Techniques; D008124:Locomotion / Q000187:drug effects / Q000235:genetics*; D010641:Phenotype; D000071456:Sequestosome-1 Protein; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000602733:SQSTM1 protein, zebrafish; D000071456:Sequestosome-1 Protein; D029961:Zebrafish Proteins; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus