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

Wong, Ching On; Palmieri, Michela; Li, Jiaxing; Akhmedov, Dmitry; Chao, Yufang; Broadhead, Geoffrey T.; Zhu, Michael X.; Berdeaux, Rebecca; Collins, Catherine A.; Sardiello, Marco; Venkatachalam, Kartik

doi:10.1016/j.celrep.2015.08.047

Cited by 27 publications

(26 citation statements)

References 70 publications

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“…Along similar lines, the observed interaction of FBN1 and TRPML1 is of interest, as FBN1 constitutes a versatile regulator of TGF-β1 signalling (full-length FBN1 sequesters TGF-β1 in microfibrils to prevent TGF signalling, while FBN1 fragments dissociate sequestered TGF-β1 to facilitate TGF signalling) [84]. While it was initially noted that trpml 1 Drosophila larvae show impaired synapse integrity reminiscent of a Drosophila mutant exhibiting impaired TGF-β regulation and synaptic recycling [81,85], the phenotype was later attributed to altered mTORC1/JNK signalling [85]. The possible interplay between TRPML1 activity and TGF-β1 signalling remains unexplored.…”

Section: R-snare Q-snarementioning

confidence: 98%

The protein interaction networks of mucolipins and two-pore channels

Krogsaeter¹,

Biel

Wahl‐Schott

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Background:The endolysosomal, non-selective cation channels, two-pore channels (TPCs) and mucolipins (TRPMLs), regulate intracellular membrane dynamics and autophagy. While partially compensatory for each other, isoform-specific intracellular distribution, cell-type expression patterns, and regulatory mechanisms suggest different channel isoforms confer distinct properties to the cell. Scope of review: Briefly, established TPC/TRPML functions and interaction partners ('interactomes') are discussed. Novel TRPML3 interactors are shown, and a meta-analysis of experimentally obtained channel interactomes conducted. Accordingly, interactomes are compared and contrasted, and subsequently described in detail for TPC1, TPC2, TRPML1, and TRPML3. Major conclusions: TPC interactomes are well-defined, encompassing intracellular membrane organisation proteins. TRPML interactomes are varied, encompassing cardiac contractility-and chaperone-mediated autophagy proteins, alongside regulators of intercellular signalling. General significance: Comprising recently proposed targets to treat cancers, infections, metabolic disease and neurodegeneration, the advancement of TPC/TRPML understanding is of considerable importance. This review proposes novel directions elucidating TPC/TRPML relevance in health and disease.

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Section: R-snare Q-snarementioning

confidence: 98%

The protein interaction networks of mucolipins and two-pore channels

Krogsaeter¹,

Biel

Wahl‐Schott

2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Conversely, in Drosophila models of Batten's disease or mucolipidosis IV, defects in autolysosomal protein degradation pathway lead to synaptic undergrowth by suppressing JNK activation. This study revealed a conserved mechanism by which lysosomal degradation of proteins to free amino acids activates MTORC1 (mechanistic target of rapamycin complex 1), which directly phosphorylates Wallenda to stimulate JNK signaling and promote synaptic growth . Finally, voltage‐gated calcium channels (VGCCs) located on the lysosomal membrane have been identified as novel regulators of autophagic flux.…”

Section: Dynamic Interplay Between Diverse Presynaptic Organelles Orcmentioning

confidence: 99%

The Crossroads of Synaptic Growth Signaling, Membrane Traffic and Neurological Disease: Insights from Drosophila

Deshpande

Rodal

2015

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Neurons require target-derived autocrine and paracrine growth factors to maintain proper identity, innervation, homeostasis and survival. Neuronal growth factor signaling is highly dependent on membrane traffic, Neurons are highly specialized cells that depend heavily on membrane traffic for multiple facets of their unique physiology: to facilitate the rapid release and recycling of neurotransmitter-containing synaptic vesicles, to maintain their extreme and polarized morphology and compartmentalization and to sustain and regulate intracellular transport and signaling over extremely long distances. In particular, endocytic traffic is required to control the localization and activity of the signaling proteins and transmembrane receptors that govern neuronal growth and survival. To maintain appropriate innervation and activity, neurons respond to target-derived paracrine and autocrine growth factors. These growth factors bind to receptors that are internalized and trafficked along the endocytic and endosomal pathways, exerting local effects at synapses as well as long-range and long-lasting effects at neuronal cell bodies (1). The Drosophila larval neuromuscular junction (NMJ) is an excellent model for studying the cell biology of growth factor receptor signaling in neurons as it is exquisitely accessible for genetic manipulation, electrophysiology and functional analyses (2). Of particular importance, this system offers unparalleled advantages for imaging neurons in their normal developmental context, as both motor axons and NMJs are found at the surface of filleted larvae for high-resolution microscopy, and are also visible through the larval cuticle in intact, anesthetized animals (3). Over the course of larval development, the muscle area grows 100-fold, requiring synaptic activity-dependent expansion of synaptic arbors via the addition of new synaptic varicosities or boutons (4, 5; Figure 1A). This expansion requires a number of growth signaling pathways at the NMJ, including (but not limited to) www.traffic.dk 87

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“…Recent work has discovered such an activity for the cAMP effector kinase protein kinase A (PKA), which can induce Wnd's activation and function, and is required for its activation in injured axons [42]. Genetic interaction studies have also led to the suggestion that Wnd may also be regulated by TORC1 [43]. It is striking that, as discussed previously, both cAMP and mTOR signaling are known for abilities to unlock axonal regeneration potential.…”

Section: Intrinsic Mechanisms Of Axon Regeneration: Discoveries From mentioning

confidence: 99%

Intrinsic mechanisms for axon regeneration: insights from injured axons in Drosophila

Hao

Collins

2017

Current Opinion in Genetics & Development

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Axonal damage and loss are common and negative consequences of neuronal injuries, and also occur in some neurodegenerative diseases. For neurons to have a chance to repair their connections, they need to survive the damage, initiate new axonal growth, and ultimately establish new synaptic connections. This review discusses how recent work in Drosophila models have informed our understanding of the cellular pathways used by neurons to respond to axonal injuries. Similarly to mammalian neurons, Drosophila neurons appear to be more limited in their capacity regrow (regenerate) damaged axons in the central nervous system, but can undergo axonal regeneration to varying extents in the peripheral nervous system. Conserved cellular pathways are activated by axonal injury via mechanisms that are specific to axons but not dendrites, and new unanticipated inhibitors of axon regeneration can be identified via genetic screening. These findings, made predominantly via genetic and live imaging methods in Drosophila, emphasize the utility of this model organism for the identification and study of basic cellular mechanisms used for neuronal repair.

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

Cited by 27 publications

References 70 publications

The protein interaction networks of mucolipins and two-pore channels

The protein interaction networks of mucolipins and two-pore channels

The Crossroads of Synaptic Growth Signaling, Membrane Traffic and Neurological Disease: Insights from Drosophila

Intrinsic mechanisms for axon regeneration: insights from injured axons in Drosophila

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