Details

Autor(en) / Beteiligte

• Borg, Rebecca
• Purkiss, Angie
• Cacciottolo, Rebecca
• Herrera, Paul
• Cauchi, Ruben J.

Titel

Loss of amyotrophic lateral sclerosis risk factor SCFD1 causes motor dysfunction in Drosophila

Ist Teil von

• Neurobiology of aging, 2023-06, Vol.126, p.67-76

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• •Common genetic variants in SCFD1 are associated with increased ALS risk•Moderate gene silencing of the fly SCFD1 orthologue Slh caused motoric defects•Severe Slh knockdown induced larval paralysis and neuromuscular junction deficits•Genes encoding chaperones are downregulated downstream of Slh ablation•Findings support notion that loss of SCFD1 function contributes to ALS pathogenesis 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.