Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction
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
Affiliations
Ching-On Wong
Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA
Michela Palmieri
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
Jiaxing Li
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
Dmitry Akhmedov
Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA
Yufang Chao
Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA
Geoffrey T. Broadhead
Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA
Michael X. Zhu
Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA
Rebecca Berdeaux
Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA
Catherine A. Collins
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA
Marco Sardiello
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
Kartik Venkatachalam
Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA
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.
