Kim Joohyung, Kim Sungdae, Nahm Minyeop, Li Tsai-Ning, Lin Hsin-Chieh, Kim Yeongjin David, Lee Jihye, Yao Chi-Kuang, Lee Seungbok
Department of Brain and Cognitive Sciences, Seoul National University, Seoul, Korea.
Department of Cell and Developmental Biology and Dental Research Institute, Seoul National University, Seoul, Korea.
J Cell Biol. 2021 May 3;220(5). doi: 10.1083/jcb.202007112.
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.
人类 ALS2 基因突变会导致隐性少年型肌萎缩侧索硬化症及相关运动神经元疾病。尽管 ALS2 蛋白已被确定为小 GTP 酶 Rab5 的鸟嘌呤核苷酸交换因子，但其生理作用仍 largely 未知。在这里，我们证明果蝇 ALS2 同源物（dALS2）通过激活卷曲蛋白核输入（FNI）途径促进突触后发育。dALS2 缺失会导致突触后亚突触网状结构（SSR）出现结构缺陷，重现 FNI 途径突变体中观察到的表型。一致地，这些发育表型通过果蝇卷曲蛋白 -2（dFz2）的信号传导活性 C 末端片段的突触后表达得以挽救。我们进一步证明 dALS2 指导早期到晚期内体运输，并且 dFz2 C 末端在晚期内体中被切割。最后，dALS2 缺失会导致与肌萎缩侧索硬化症相似的年龄依赖性进行性缺陷，包括运动障碍和脑神经元变性，且与 FNI 途径无关。这些发现确立了 dALS2 在内涵体运输、突触发育和神经元存活中的新调控作用。
