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Cell Rep. 2015 Sep 29;12(12):2009-20. doi: 10.1016/j.celrep.2015.08.047. Epub 2015 Sep 17.

Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction.

Author information

1
Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA.
2
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.
3
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
4
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.
5
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.

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.

PMID:
26387958
PMCID:
PMC4591237
DOI:
10.1016/j.celrep.2015.08.047
[Indexed for MEDLINE]
Free PMC Article

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