Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta; Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
Centre for Molecular Medicine and Biobanking, Biomedical Sciences Building, University of Malta, Msida, Malta; Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta.
Neurobiol Aging. 2023 Jun;126:67-76. doi: 10.1016/j.neurobiolaging.2023.02.005. Epub 2023 Feb 21.
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.
肌萎缩侧索硬化症（ALS）是一种进行性神经肌肉疾病，主要由遗传、环境和生活方式因素之间的复杂相互作用引起。在最广泛的全基因组关联研究（GWAS）中，Sec1 家族结构域包含 1 基因（SCFD1）中的常见遗传变异与 ALS 风险增加有关。SCFD1 也被确定为 ALS 的最重要的表达数量性状基因座（eQTL）。SCFD1 功能的丧失是否直接导致运动系统功能障碍仍未解决。在这里，我们表明，果蝇 SCFD1 同源物 Slh 的中度基因沉默足以导致成年果蝇的攀爬和飞行缺陷。更严重的敲低导致幼虫在变态前死亡前的运动能力显著降低和严重的神经肌肉接头（NMJ）缺陷。RNA-seq 显示编码伴侣蛋白的基因下调，这些伴侣蛋白介导 Slh 消融下游的蛋白质折叠。我们的研究结果支持这样的观点，即 SCFD1 功能的丧失是 ALS 的一个有意义的贡献，疾病易感性可能是由于保护机制受到破坏，导致错误折叠和蛋白质聚集。
