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Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal
Ching-On Wong1, Michela Palmieri2, Jiaxing Li3
1Department of Integrative Biology and Pharmacology, University of Texas School of Medicine, Houston, TX 77030, USA.
Cell Reports
|September 22, 2015
Summary
Lysosomes are crucial for nerve growth in models of lysosomal storage diseases (LSDs). Targeting anaplastic lymphoma kinase (ALK) may treat neurodevelopmental deficits by linking nerve growth to dietary protein.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Lysosomal storage diseases (LSDs) cause neurodevelopmental deficits.
- Lysosomes play a role in cellular homeostasis and signaling pathways.
Purpose of the Study:
- To investigate the mechanisms underlying neurodevelopmental deficits in LSDs.
- To identify the role of lysosomes in neuronal development and growth.
Main Methods:
- Utilized Drosophila and mouse models of LSDs.
- Examined the involvement of Rag GTPases, MTORC1, JNK, and ALK pathways.
- Assessed the impact of dietary protein and ALK inhibition on NMJ development.
Main Results:
- Lysosomes promote neuromuscular junction (NMJ) growth through MTORC1 signaling.
- MTORC1 stimulates NMJ growth via JNK, not S6K/4E-BP1, a conserved mechanism.
- NMJ development is insensitive to dietary protein due to ALK restricting amino acid uptake.
- ALK inhibition restores sensitivity of NMJ development to dietary protein.
Conclusions:
- Lysosomal dysfunction contributes to neurodevelopmental deficits in LSDs.
- The MTORC1-JNK pathway regulated by lysosomes is critical for axonal growth.
- ALK is a key regulator of neuronal amino acid uptake and NMJ development.
- Targeting ALK presents a potential therapeutic strategy for LSDs.
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