Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction.
Diminished MTORC1-Dependent JNK Activation Underlies the Neurodevelopmental Defects Associated with Lysosomal Dysfunction.
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MTORC1 依赖性 JNK 激活减少是与溶酶体功能障碍相关的神经发育缺陷的基础。
DOI：
10.1016/j.celrep.2015.08.047
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发表时间：
2015
期刊：
影响因子：
8.8
通讯作者：
Venkatachalam,Kartik
中科院分区：
文献类型：
--
作者：
Wong,Ching-On;Palmieri,Michela;Li,Jiaxing;Akhmedov,Dmitry;Chao,Yufang;Broadhead,GeoffreyT;Zhu,MichaelX;Berdeaux,Rebecca;Collins,CatherineA;Sardiello,Marco;Venkatachalam,Kartik
Here, we evaluate the mechanisms underlying the neurodevelopmental deficits inDrosophilaand 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 inDrosophilaand 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.
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Xu, Haoxing
影响因子：
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H. Mitchison;P. E. Taschner;Gabriel Kremmidiotis;D. F. Callen;Na Doggett;Terry J. Lerner;Janes Rb;Bonnie A. Wallace;P. Munroe;A. O'rawe;RM Gardiner;Sara E. Mole
影响因子：
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作者：
Yip CK;Murata K;Walz T;Sabatini DM;Kang SA
通讯作者：
Kang SA
影响因子：
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作者：
Sun, M;Goldin, E;Slaugenhaupt, SA
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