ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival
| Autor: | Sung-Dae Kim, Chi-Kuang Yao, Yeongjin David Kim, Minyeop Nahm, Hsin-Chieh Lin, Joohyung Kim, Tsai-Ning Li, Jihye Lee, Seungbok Lee |
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| Rok vydání: | 2021 |
| Předmět: |
Frizzled
Cell Survival Endosome Endosomes Biology Article 03 medical and health sciences 0302 clinical medicine Postsynaptic potential medicine Animals Guanine Nucleotide Exchange Factors Small GTPase Cells Cultured Late endosome rab5 GTP-Binding Proteins 030304 developmental biology Neurons 0303 health sciences Trafficking Cell Death Amyotrophic Lateral Sclerosis Neurodegeneration Post-Synaptic Density Biological Transport Cell Biology medicine.disease Cell biology Phenotype Mutation Drosophila Guanine nucleotide exchange factor Nuclear transport 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.202007112 |
| Popis: | Postsynaptic development requires the Frizzled nuclear import (FNI) pathway entailing the internalization and subsequent cleavage of Frizzled-2. Kim et al. show that Drosophila ALS2 regulates postsynaptic development by directing Frizzled-2 trafficking to late endosomes, where the Frizzled-2 C terminus is cleaved, and also promotes neuronal survival independently of the FNI pathway. 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. |
| Databáze: | OpenAIRE |
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