PUBLICATION
Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD
- Authors
- Lattante, S., de Calbiac, H., Le Ber, I., Brice, A., Ciura, S., Kabashi, E.
- ID
- ZDB-PUB-141121-2
- Date
- 2015
- Source
- Human molecular genetics 24(6): 1682-90 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics*
- Amyotrophic Lateral Sclerosis/drug therapy
- Amyotrophic Lateral Sclerosis/genetics*
- Animals
- Disease Models, Animal
- Frontotemporal Lobar Degeneration/drug therapy
- Frontotemporal Lobar Degeneration/genetics*
- Gene Knockdown Techniques
- Locomotion/drug effects
- Locomotion/genetics*
- Phenotype
- Sirolimus/pharmacology*
- TOR Serine-Threonine Kinases/metabolism
- Zebrafish/genetics
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 25410659 Full text @ Hum. Mol. Genet.
Citation
Lattante, S., de Calbiac, H., Le Ber, I., Brice, A., Ciura, S., Kabashi, E. (2015) Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD. Human molecular genetics. 24(6):1682-90.
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 impairing 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping