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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Calcium-Binding Proteins
  • Dietary Proteins / administration & dosage
  • Disease Models, Animal
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Gene Expression Regulation
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Lysosomal Storage Diseases, Nervous System / genetics*
  • Lysosomal Storage Diseases, Nervous System / metabolism
  • Lysosomal Storage Diseases, Nervous System / pathology
  • Lysosomes / drug effects
  • Lysosomes / metabolism*
  • Lysosomes / pathology
  • MAP Kinase Kinase 4 / genetics*
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / genetics*
  • Multiprotein Complexes / metabolism
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / genetics*
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / pathology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction
  • Synapses / drug effects
  • Synapses / metabolism
  • Synapses / pathology
  • TOR Serine-Threonine Kinases / genetics*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Calcium-Binding Proteins
  • Dietary Proteins
  • Dlk1 protein, mouse
  • Drosophila Proteins
  • Intercellular Signaling Peptides and Proteins
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • TOR Serine-Threonine Kinases
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • MAP Kinase Kinase Kinases
  • wnd protein, Drosophila
  • MAP Kinase Kinase 4