title: Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction.
abstract: 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.
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA.
authors.forename: Ching-On
authors.initials: CO
authors.lastname: Wong
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, TX 77030, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Palmieri
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Akhmedov
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Broadhead
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA; Program in Cell and Regulatory Biology (CRB), Graduate School of Biomedical Sciences, University of Texas School of Medicine, Houston, TX 77030, USA.
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA; Program in Cell and Regulatory Biology (CRB), Graduate School of Biomedical Sciences, University of Texas School of Medicine, Houston, TX 77030, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Berdeaux
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Collins
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, TX 77030, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Sardiello
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA; Program in Cell and Regulatory Biology (CRB), Graduate School of Biomedical Sciences, University of Texas School of Medicine, Houston, TX 77030, USA; Program in Neuroscience, Graduate School of Biomedical Sciences, University of Texas School of Medicine, Houston, TX 77030, USA. Electronic address: kartik.venkatachalam@uth.tmc.edu.
authors.forename: Kartik
authors.initials: K
authors.lastname: Venkatachalam
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002135:Calcium-Binding Proteins; D004044:Dietary Proteins / Q000008:administration & dosage; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020140:Lysosomal Storage Diseases, Nervous System / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D004044:Dietary Proteins; C512925:Dlk1 protein, mouse; D029721:Drosophila Proteins; D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; C512899:wnd protein, Drosophila; D048670:MAP Kinase Kinase 4