Institute for Neurosciences Montpellier, Institut National de la Santé et de la Recherche Médicale, Université Montpellier, Montpellier, France.
Service de Biochimie et Biologie Moléculaire, CHU Nîmes, Université Montpellier, Nîmes, France.
Sci Rep. 2024 Aug 22;14(1):19540. doi: 10.1038/s41598-024-70543-y.
Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by the death of motoneurons. Several mutations in the KIF5A gene have been identified in patients with ALS. Some mutations affect the splicing sites of exon 27 leading to its deletion (Δ27 mutation). KIF5A Δ27 is aggregation-prone and pathogenic for motoneurons due to a toxic gain of function. Another mutation found to be enriched in ALS patients is a proline/leucine substitution at position 986 (P986L mutation). Bioinformatic analyses strongly suggest that this variant is benign. Our study aims to conduct functional studies in Drosophila to classify the KIF5A P986L variant. When expressed in motoneurons, KIF5A P986L does not modify the morphology of larval NMJ or the synaptic transmission. In addition, KIF5A P986L is uniformly distributed in axons and does not disturb mitochondria distribution. Locomotion at larval and adult stages is not affected by KIF5A P986L. Finally, both KIF5A WT and P986L expression in adult motoneurons extend median lifespan compared to control flies. Altogether, our data show that the KIF5A P986L variant is not pathogenic for motoneurons and may represent a hypomorphic allele, although it is not causative for ALS.
肌萎缩侧索硬化症（ALS）是一种由运动神经元死亡引起的毁灭性瘫痪性疾病。在 ALS 患者中已经鉴定出 KIF5A 基因的几个突变。一些突变影响外显子 27 的剪接位点，导致其缺失（Δ27 突变）。由于功能获得性毒性，KIF5A Δ27 易于聚集并对运动神经元致病。另一种在 ALS 患者中富集的突变是位于 986 位的脯氨酸/亮氨酸取代（P986L 突变）。生物信息学分析强烈表明该变体是良性的。我们的研究旨在通过在果蝇中进行功能研究来对 KIF5A P986L 变体进行分类。当在运动神经元中表达时，KIF5A P986L 不会改变幼虫 NMJ 的形态或突触传递。此外，KIF5A P986L 在轴突中均匀分布，不会干扰线粒体分布。幼虫和成虫阶段的运动不受 KIF5A P986L 的影响。最后，与对照果蝇相比，KIF5A WT 和 P986L 在成年运动神经元中的表达均延长了中位寿命。总之，我们的数据表明 KIF5A P986L 变体对运动神经元没有致病性，可能代表一个低功能等位基因，尽管它不是 ALS 的病因。
