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ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival

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 d...

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Autores principales: Kim, Joohyung, Kim, Sungdae, Nahm, Minyeop, Li, Tsai-Ning, Lin, Hsin-Chieh, Kim, Yeongjin David, Lee, Jihye, Yao, Chi-Kuang, Lee, Seungbok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944400/
https://www.ncbi.nlm.nih.gov/pubmed/33683284
http://dx.doi.org/10.1083/jcb.202007112
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author Kim, Joohyung
Kim, Sungdae
Nahm, Minyeop
Li, Tsai-Ning
Lin, Hsin-Chieh
Kim, Yeongjin David
Lee, Jihye
Yao, Chi-Kuang
Lee, Seungbok
author_facet Kim, Joohyung
Kim, Sungdae
Nahm, Minyeop
Li, Tsai-Ning
Lin, Hsin-Chieh
Kim, Yeongjin David
Lee, Jihye
Yao, Chi-Kuang
Lee, Seungbok
author_sort Kim, Joohyung
collection PubMed
description 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.
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spelling pubmed-79444002021-11-03 ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival Kim, Joohyung Kim, Sungdae Nahm, Minyeop Li, Tsai-Ning Lin, Hsin-Chieh Kim, Yeongjin David Lee, Jihye Yao, Chi-Kuang Lee, Seungbok J Cell Biol Article 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. Rockefeller University Press 2021-03-08 /pmc/articles/PMC7944400/ /pubmed/33683284 http://dx.doi.org/10.1083/jcb.202007112 Text en © 2021 Kim et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Kim, Joohyung
Kim, Sungdae
Nahm, Minyeop
Li, Tsai-Ning
Lin, Hsin-Chieh
Kim, Yeongjin David
Lee, Jihye
Yao, Chi-Kuang
Lee, Seungbok
ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival
title ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival
title_full ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival
title_fullStr ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival
title_full_unstemmed ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival
title_short ALS2 regulates endosomal trafficking, postsynaptic development, and neuronal survival
title_sort als2 regulates endosomal trafficking, postsynaptic development, and neuronal survival
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944400/
https://www.ncbi.nlm.nih.gov/pubmed/33683284
http://dx.doi.org/10.1083/jcb.202007112
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