Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction
Here, we evaluate the mechanisms underlying the neurodevelopmental deficits in Drosophila and mouse models of lysosomal storage diseases (LSDs). We find that lysosomes promote the growth of neuromuscular junctions (NMJs) via Rag GTPases and mechanistic target of rapamycin complex 1 (MTORC1). However...
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doaj-6e39c47238c748c48204c393897d63d02020-11-24T21:30:32ZengElsevierCell Reports2211-12472015-09-0112122009202010.1016/j.celrep.2015.08.047Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal DysfunctionChing-On Wong0Michela Palmieri1Jiaxing Li2Dmitry Akhmedov3Yufang Chao4Geoffrey T. Broadhead5Michael X. Zhu6Rebecca Berdeaux7Catherine A. Collins8Marco Sardiello9Kartik Venkatachalam10Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, TX 77030, USADepartment of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USADepartment of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USADepartment of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USADepartment of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USADepartment of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USADepartment of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, TX 77030, USADepartment of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USAHere, we evaluate the mechanisms underlying the neurodevelopmental deficits in Drosophila and mouse models of lysosomal storage diseases (LSDs). We find that lysosomes promote the growth of neuromuscular junctions (NMJs) via Rag GTPases and mechanistic target of rapamycin complex 1 (MTORC1). However, rather than employing S6K/4E-BP1, MTORC1 stimulates NMJ growth via JNK, a determinant of axonal growth in Drosophila and mammals. This role of lysosomal function in regulating JNK phosphorylation is conserved in mammals. Despite requiring the amino-acid-responsive kinase MTORC1, NMJ development is insensitive to dietary protein. We attribute this paradox to anaplastic lymphoma kinase (ALK), which restricts neuronal amino acid uptake, and the administration of an ALK inhibitor couples NMJ development to dietary protein. Our findings provide an explanation for the neurodevelopmental deficits in LSDs and suggest an actionable target for treatment.http://www.sciencedirect.com/science/article/pii/S2211124715009328 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ching-On Wong Michela Palmieri Jiaxing Li Dmitry Akhmedov Yufang Chao Geoffrey T. Broadhead Michael X. Zhu Rebecca Berdeaux Catherine A. Collins Marco Sardiello Kartik Venkatachalam |
spellingShingle |
Ching-On Wong Michela Palmieri Jiaxing Li Dmitry Akhmedov Yufang Chao Geoffrey T. Broadhead Michael X. Zhu Rebecca Berdeaux Catherine A. Collins Marco Sardiello Kartik Venkatachalam Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction Cell Reports |
author_facet |
Ching-On Wong Michela Palmieri Jiaxing Li Dmitry Akhmedov Yufang Chao Geoffrey T. Broadhead Michael X. Zhu Rebecca Berdeaux Catherine A. Collins Marco Sardiello Kartik Venkatachalam |
author_sort |
Ching-On Wong |
title |
Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction |
title_short |
Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction |
title_full |
Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction |
title_fullStr |
Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction |
title_full_unstemmed |
Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction |
title_sort |
diminished mtorc1-dependent jnk activation underlies the neurodevelopmental defects associated with lysosomal dysfunction |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2015-09-01 |
description |
Here, we evaluate the mechanisms underlying the neurodevelopmental deficits in Drosophila and mouse models of lysosomal storage diseases (LSDs). We find that lysosomes promote the growth of neuromuscular junctions (NMJs) via Rag GTPases and mechanistic target of rapamycin complex 1 (MTORC1). However, rather than employing S6K/4E-BP1, MTORC1 stimulates NMJ growth via JNK, a determinant of axonal growth in Drosophila and mammals. This role of lysosomal function in regulating JNK phosphorylation is conserved in mammals. Despite requiring the amino-acid-responsive kinase MTORC1, NMJ development is insensitive to dietary protein. We attribute this paradox to anaplastic lymphoma kinase (ALK), which restricts neuronal amino acid uptake, and the administration of an ALK inhibitor couples NMJ development to dietary protein. Our findings provide an explanation for the neurodevelopmental deficits in LSDs and suggest an actionable target for treatment. |
url |
http://www.sciencedirect.com/science/article/pii/S2211124715009328 |
work_keys_str_mv |
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