Loss of amyotrophic lateral sclerosis risk factor SCFD1 causes motor dysfunction in Drosophila.
Neurobiol Aging
; 126: 67-76, 2023 06.
Article
em En
| MEDLINE
| ID: mdl-36944290
ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease mostly resulting from a complex interplay between genetic, environmental and lifestyle factors. Common genetic variants in the Sec1 Family Domain Containing 1 (SCFD1) gene have been associated with increased ALS risk in the most extensive genome-wide association study (GWAS). SCFD1 was also identified as a top-most significant expression Quantitative Trait Locus (eQTL) for ALS. Whether loss of SCFD1 function directly contributes to motor system dysfunction remains unresolved. Here we show that moderate gene silencing of Slh, the Drosophila orthologue of SCFD1, is sufficient to cause climbing and flight defects in adult flies. A more severe knockdown induced a significant reduction in larval mobility and profound neuromuscular junction (NMJ) deficits prior to death before metamorphosis. RNA-seq revealed downregulation of genes encoding chaperones that mediate protein folding downstream of Slh ablation. Our findings support the notion that loss of SCFD1 function is a meaningful contributor to ALS and disease predisposition may result from erosion of the mechanisms protecting against misfolding and protein aggregation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esclerose Lateral Amiotrófica
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Neurobiol Aging
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Malta