Mutations in the human ALS2 gene cause recessive juvenile-onset amyotrophic lateral sclerosis and related motor neuron diseases. Although the ALS2 protein has been identified as a guanine-nucleotide exchange factor for the small GTPase Rab5, its physiological roles remain largely unknown. Here, we demonstrate that the Drosophila homologue of ALS2 (dALS2) promotes postsynaptic development by activating the Frizzled nuclear import (FNI) pathway. dALS2 loss causes structural defects in the postsynaptic subsynaptic reticulum (SSR), recapitulating the phenotypes observed in FNI pathway mutants. Consistently, these developmental phenotypes are rescued by postsynaptic expression of the signaling-competent C-terminal fragment of Drosophila Frizzled-2 (dFz2). We further demonstrate that dALS2 directs early to late endosome trafficking and that the dFz2 C terminus is cleaved in late endosomes. Finally, dALS2 loss causes age-dependent progressive defects resembling ALS, including locomotor impairment and brain neurodegeneration, independently of the FNI pathway. These findings establish novel regulatory roles for dALS2 in endosomal trafficking, synaptic development, and neuronal survival.

中文翻译：

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ALS2调节内体运输，突触后发育和神经元存活。

人类ALS2基因的突变会引起隐性少年性肌萎缩性侧索硬化症和相关的运动神经元疾病。尽管已将ALS2蛋白鉴定为小GTPase Rab5的鸟嘌呤-核苷酸交换因子，但其生理作用仍然未知。在这里，我们证明了果蝇ALS2（dALS2）的同源物通过激活卷曲的核导入（FNI）途径促进突触后发育。dALS2丢失导致突触后突触网状结构（SSR）中的结构缺陷，概括了在FNI途径突变体中观察到的表型。一致地，通过果蝇Frizzled-2（dFz2）的有信号能力的C端片段的突触后表达来挽救这些发育表型。我们进一步证明，dALS2指导早期至晚期内体运输，并且dFz2 C末端在晚期内体中裂解。最后，dALS2缺失会导致与年龄相关的类似于ALS的进行性缺陷，包括运动障碍和脑神经变性，而与FNI途径无关。这些发现建立了dALS2在内体运输，突触发育和神经元存活中的新型调控作用。