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Wong, C.O., Palmieri, M., Li, J., Akhmedov, D., Chao, Y., Broadhead, G.T., Zhu, M.X., Berdeaux, R., Collins, C.A., Sardiello, M., Venkatachalam, K. (2015). Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction.  Cell Rep. 12(12): 2009--2020.
FlyBase ID
FBrf0229723
Publication Type
Research paper
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.

Graphical Abstract
Obtained with permission from Cell Press.
PubMed ID
PubMed Central ID
PMC4591237 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Cell Rep.
    Title
    Cell reports
    ISBN/ISSN
    2211-1247
    Data From Reference