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

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease mostly resulting from a com-plex 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 ex-tensive genome-wide association study (GWAS). SCFD1 was also identified as a top-most significant ex-pression 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 se-vere 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 encod-ing 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.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

This study found that genetic variations in the SCFD1 gene are associated with an increased risk of amyotrophic lateral sclerosis (ALS). Gene silencing experiments in fruit flies showed that loss of SCFD1 function can cause motor defects and neuromuscular junction deficits. The study also suggests that SCFD1 dysfunction may contribute to ALS through protein misfolding.