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

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish
Pages (from-to)2009-2020
Number of pages12
JournalCell Reports
Volume12
Issue number12
DOIs
StatePublished - Sep 29 2015

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