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Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD.

Hum. Mol. Genet.2015 Mar 15;24(6):1682-90. Epub 2014 Nov 19
Serena Lattante 1 , Hortense de Calbiac 1 , Isabelle Le Ber 2 , Alexis Brice 3 , Sorana Ciura 4 , Edor Kabashi 4
Serena Lattante 1 , Hortense de Calbiac 1 , Isabelle Le Ber 2 , Alexis Brice 3 , Sorana Ciura 4 , Edor Kabashi 4
+ et al

[No authors listed]

Author information
  • 1 Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM; Inserm, U 1127, ICM; Cnrs, UMR 7225, ICM; ICM, Paris, F-75013 Paris, France.
  • 2 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.
  • 3 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.
  • 4 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.

摘要


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.