Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Genet Genomics ; 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38925347

RESUMO

Dendritic morphology is typically highly branched, and the branching and synaptic abundance of dendrites can enhance the receptive range of neurons and the diversity of information received, thus providing the basis for information processing in the nervous system. Once dendritic development is aberrantly compromised or damaged, it may lead to abnormal connectivity of the neural network, affecting the function and stability of the nervous system and ultimately triggering a series of neurological disorders. Research on the regulation of dendritic developmental processes has flourished, and much progress is now being made in its regulatory mechanisms. Noteworthily, dendrites are characterized by an extremely complex dendritic arborization that cannot be attributed to individual protein functions alone, requiring a systematic analysis of the intrinsic and extrinsic signals and the coordinated roles among them. Actin cytoskeleton organization and membrane vesicle trafficking are required during dendrite development, with actin providing tracks for vesicles and vesicle trafficking in turn providing material for actin assembly. In this review, we focus on these two basic biological processes and discuss the molecular mechanisms and their synergistic effects underlying the morphogenesis of neuronal dendrites. We also offer insights and discuss strategies for the potential preventive and therapeutic treatment of neuropsychiatric disorders.

2.
iScience ; 27(2): 108944, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38318379

RESUMO

Synapses are fundamental components of the animal nervous system. Synaptic cytoskeleton is essential for maintaining proper neuronal development and wiring. Perturbations in neuronal microtubules (MTs) are correlated with numerous neuropsychiatric disorders. Despite discovering multiple synaptic MT regulators, the importance of MT stability, and particularly the polarity of MT in synaptic function, is still under investigation. Here, we identify Patronin, an MT minus-end-binding protein, for its essential role in presynaptic regulation of MT organization and neuromuscular junction (NMJ) development. Analyses indicate that Patronin regulates synaptic development independent of Klp10A. Subsequent research elucidates that it is short stop (Shot), a member of the Spectraplakin family of large cytoskeletal linker molecules, works synergistically with Patronin to govern NMJ development. We further raise the possibility that normal synaptic MT polarity contributes to proper NMJ morphology. Overall, this study demonstrates an unprecedented role of Patronin, and a potential involvement of MT polarity in synaptic development.

3.
iScience ; 27(1): 108545, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38213621

RESUMO

Stem cells are heterogeneous to generate diverse differentiated cell types required for organogenesis; however, the underlying mechanisms that differently maintain these heterogeneous stem cells are not well understood. In this study, we identify that Golgi-to-endoplasmic reticulum (ER) retrograde transport specifically maintains type II neuroblasts (NBs) through the Notch signaling. We reveal that intermediate neural progenitors (INPs), immediate daughter cells of type II NBs, provide Delta and function as the NB niche. The Delta used by INPs is mainly produced by NBs and asymmetrically distributed to INPs. Blocking retrograde transport leads to a decrease in INP number, which reduces Notch activity and results in the premature differentiation of type II NBs. Furthermore, the reduction of Delta could suppress tumor formation caused by type II NBs. Our results highlight the crosstalk between Golgi-to-ER retrograde transport, Notch signaling, stem cell niche, and fusion as an essential step in maintaining the self-renewal of type II NB lineage.

4.
Commun Biol ; 6(1): 1056, 2023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37853189

RESUMO

Neuroligins are transmembrane cell adhesion proteins well-known for their genetic links to autism spectrum disorders. Neuroligins can function by regulating the actin cytoskeleton, however the factors and mechanisms involved are still largely unknown. Here, using the Drosophila neuromuscular junction as a model, we reveal that F-Actin assembly at the Drosophila NMJ is controlled through Cofilin signaling mediated by an interaction between DNlg2 and RACK1, factors not previously known to work together. The deletion of DNlg2 displays disrupted RACK1-Cofilin signaling pathway with diminished actin cytoskeleton proteo-stasis at the terminal of the NMJ, aberrant NMJ structure, reduced synaptic transmission, and abnormal locomotion at the third-instar larval stage. Overexpression of wildtype and activated Cofilin in muscles are sufficient to rescue the morphological and physiological defects in dnlg2 mutants, while inactivated Cofilin is not. Since the DNlg2 paralog DNlg1 is known to regulate F-actin assembly mainly via a specific interaction with WAVE complex, our present work suggests that the orchestration of F-actin by Neuroligins is a diverse and complex process critical for neural connectivity.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/genética , Drosophila/metabolismo , Fatores de Despolimerização de Actina/genética , Fatores de Despolimerização de Actina/metabolismo , Actinas/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Transdução de Sinais/fisiologia , Receptores de Quinase C Ativada/genética
5.
Int J Mol Sci ; 24(17)2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37686022

RESUMO

Developmental remodeling of neurite is crucial for the accurate wiring of neural circuits in the developing nervous system in both vertebrates and invertebrates, and may also contribute to the pathogenesis of neuropsychiatric disorders, for instance, autism, Alzheimer's disease (AD), and schizophrenia. However, the molecular underpinnings underlying developmental remodeling are still not fully understood. Here, we have identified DnaJ-like-2 (Droj2), orthologous to human DNAJA1 and DNAJA4 that is predicted to be involved in protein refolding, as a developmental signal promoting dendrite sculpting of the class IV dendritic arborization (C4da) sensory neuron in Drosophila. We further show that Arf102F, a GTP-binding protein previously implicated in protein trafficking, serves downstream of Droj2 to govern neurite pruning of C4da sensory neurons. Intriguingly, our data consistently demonstrate that both Droj2 and Arf102F promote the downregulation of the conserved L1-type cell-adhesion molecule Neuroglian anterior to dendrite pruning. Mechanistically, Droj2 genetically interacts with Arf102F and promotes Neuroglian downregulation to initiate dendrite severing. Taken together, this systematic study sheds light on an unprecedented function of Droj2 and Arf102F in neuronal development.


Assuntos
Neuritos , Animais , Humanos , Doença de Alzheimer , Drosophila , Proteínas de Ligação ao GTP , Molécula L1 de Adesão de Célula Nervosa , Neuritos/metabolismo , Células Receptoras Sensoriais , Proteínas de Drosophila
6.
Biol Open ; 12(1)2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36606515

RESUMO

Developmental neuronal pruning is a process by which neurons selectively remove excessive or unnecessary neurite without causing neuronal death. Importantly, this process is widely used for the refinement of neural circuits in both vertebrates and invertebrates, and may also contribute to the pathogenesis of neuropsychiatric disorders, such as autism and schizophrenia. In the peripheral nervous system (PNS), class IV dendritic arborization (da) sensory neurons of Drosophila, selectively remove the dendrites without losing their somas and axons, while the dendrites and axons of mushroom body (MB) γ neuron in the central nervous system (CNS) are eliminated by localized fragmentation during metamorphosis. Alternatively, dendrite pruning of ddaC neurons is usually investigated via live-cell imaging, while dissection and fixation are currently used for evaluating MB γ neuron axon pruning. Thus, an excellent model system to assess axon specific pruning directly via live-cell imaging remains elusive. Here, we report that the Drosophila motor neuron offers a unique advantage for studying axon pruning. Interestingly, we uncover that long-range projecting axon bundle from soma at ventral nerve cord (VNC), undergoes degeneration rather than retraction during metamorphosis. Strikingly, the pruning process of the motor axon bundle is straightforward to investigate via live imaging and it occurs approximately at 22 h after pupal formation (APF), when axon bundles are completely cleared. Consistently, the classical axon pruning regulators in the Drosophila MB γ neuron, including TGF-ß signaling, ecdysone signaling, JNK signaling, and the ubiquitin-proteasome system are also involved in governing motor axon pruning. Finally, our findings establish an unprecedented axon pruning mode that will serve to systematically screen and identify undiscovered axon pruning regulators. This article has an associated First Person interview with the first author of the paper.


Assuntos
Axônios , Drosophila , Animais , Drosophila/fisiologia , Neurônios Motores , Neuritos , Plasticidade Neuronal
7.
Sci Rep ; 11(1): 4709, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33633260

RESUMO

Cannabinoids have an important role in regulating feeding behaviors via cannabinoid receptors in mammals. Cannabinoids also exhibit potential therapeutic functions in Drosophila melanogaster, or fruit fly that lacks cannabinoid receptors. However, it remains unclear whether cannabinoids affect food consumption and metabolism in a cannabinoid receptors-independent manner in flies. In this study, we systematically investigated pharmacological functions of various cannabinoids in modulating food preference and consumption in flies. We show that flies display preferences for consuming cannabinoids, independent of two important sensory regulators Poxn and Orco. Interestingly, phyto- and endo- cannabinoids exhibit an inhibitory effect on food intake. Unexpectedly, the non-selective CB1 receptor antagonist AM251 attenuates the suppression of food intake by endocannabinoids. Moreover, the endocannabinoid anandamide (AEA) and its metabolite inhibit food intake and promote resistance to starvation, possibly through reduced lipid metabolism. Thus, this study has provided insights into a pharmacological role of cannabinoids in feeding behaviors using an adult Drosophila model.


Assuntos
Canabinoides/farmacologia , Drosophila melanogaster/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Animais , Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Drosophila melanogaster/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Endocanabinoides/farmacologia , Masculino , Alcamidas Poli-Insaturadas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo
8.
Development ; 147(19)2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32928906

RESUMO

Neuronal pruning is essential for proper wiring of the nervous systems in invertebrates and vertebrates. Drosophila ddaC sensory neurons selectively prune their larval dendrites to sculpt the nervous system during early metamorphosis. However, the molecular mechanisms underlying ddaC dendrite pruning remain elusive. Here, we identify an important and cell-autonomous role of the membrane protein Raw in dendrite pruning of ddaC neurons. Raw appears to regulate dendrite pruning via a novel mechanism, which is independent of JNK signaling. Importantly, we show that Raw promotes endocytosis and downregulation of the conserved L1-type cell-adhesion molecule Neuroglian (Nrg) prior to dendrite pruning. Moreover, Raw is required to modulate the secretory pathway by regulating the integrity of secretory organelles and efficient protein secretion. Mechanistically, Raw facilitates Nrg downregulation and dendrite pruning in part through regulation of the secretory pathway. Thus, this study reveals a JNK-independent role of Raw in regulating the secretory pathway and thereby promoting dendrite pruning.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Proteínas de Drosophila/metabolismo , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/metabolismo , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Endocitose/genética , Endocitose/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Metamorfose Biológica/genética , Metamorfose Biológica/fisiologia , Via Secretória/genética , Via Secretória/fisiologia
9.
EMBO J ; 39(10): e103549, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32267553

RESUMO

Drosophila class IV ddaC neurons selectively prune all larval dendrites to refine the nervous system during metamorphosis. During dendrite pruning, severing of proximal dendrites is preceded by local microtubule (MT) disassembly. Here, we identify an unexpected role of Mini spindles (Msps), a conserved MT polymerase, in governing dendrite pruning. Msps associates with another MT-associated protein TACC, and both stabilize each other in ddaC neurons. Moreover, Msps and TACC are required to orient minus-end-out MTs in dendrites. We further show that the functions of msps in dendritic MT orientation and dendrite pruning are antagonized by the kinesin-13 MT depolymerase Klp10A. Excessive MT depolymerization, which is induced by pharmacological treatment and katanin overexpression, also perturbs dendritic MT orientation and dendrite pruning, phenocopying msps mutants. Thus, we demonstrate that the MT polymerase Msps is required to form dendritic minus-end-out MTs and thereby promotes dendrite pruning in Drosophila sensory neurons.


Assuntos
Dendritos/fisiologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila/crescimento & desenvolvimento , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Animais , Drosophila/genética , Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Katanina/metabolismo , Cinesinas/metabolismo , Microtúbulos/metabolismo , Mutação , Plasticidade Neuronal
10.
EMBO Rep ; 21(5): e48843, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32187821

RESUMO

Pruning that selectively eliminates inappropriate projections is crucial for sculpting neural circuits during development. During Drosophila metamorphosis, ddaC sensory neurons undergo dendrite-specific pruning in response to the steroid hormone ecdysone. However, the understanding of the molecular mechanisms underlying dendrite pruning remains incomplete. Here, we show that protein phosphatase 2A (PP2A) is required for dendrite pruning. The catalytic (Microtubule star/Mts), scaffolding (PP2A-29B), and two regulatory subunits (Widerborst/Wdb and Twins/Tws) play important roles in dendrite pruning. Functional analyses indicate that PP2A, via Wdb, facilitates the expression of Sox14 and Mical prior to dendrite pruning. Furthermore, PP2A, via Tws, governs the minus-end-out orientation of microtubules (MTs) in the dendrites. Moreover, the levels of Klp10A, a MT depolymerase, increase when PP2A is compromised. Attenuation of Klp10A fully rescues the MT orientation defects in mts or pp2a-29b RNAi ddaC neurons, suggesting that PP2A governs dendritic MT orientation by suppressing Klp10A levels and/or function. Taken together, this study sheds light on a novel function of PP2A in regulating dendrite pruning and dendritic MT polarity in sensory neurons.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Dendritos , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Cinesinas , Microtúbulos , Plasticidade Neuronal , Proteína Fosfatase 2/genética
11.
Elife ; 82019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30920370

RESUMO

Class IV ddaC neurons specifically prune larval dendrites without affecting axons during Drosophila metamorphosis. ddaCs distribute the minus ends of microtubules (MTs) to dendrites but the plus ends to axons. However, a requirement of MT minus-end-binding proteins in dendrite-specific pruning remains completely unknown. Here, we identified Patronin, a minus-end-binding protein, for its crucial and dose-sensitive role in ddaC dendrite pruning. The CKK domain is important for Patronin's function in dendrite pruning. Moreover, we show that both patronin knockdown and overexpression resulted in a drastic decrease of MT minus ends and a concomitant increase of plus-end-out MTs in ddaC dendrites, suggesting that Patronin stabilizes dendritic minus-end-out MTs. Consistently, attenuation of Klp10A MT depolymerase in patronin mutant neurons significantly restored minus-end-out MTs in dendrites and thereby rescued dendrite-pruning defects. Thus, our study demonstrates that Patronin orients minus-end-out MT arrays in dendrites to promote dendrite-specific pruning mainly through antagonizing Klp10A activity. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that minor issues remain unresolved (see decision letter).


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Plasticidade Neuronal , Animais , Cinesinas/metabolismo
12.
Elife ; 72018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29537369

RESUMO

Neuroligins are postsynaptic adhesion molecules that are essential for postsynaptic specialization and synaptic function. But the underlying molecular mechanisms of neuroligin functions remain unclear. We found that Drosophila Neuroligin 1 (DNlg1) regulates synaptic structure and function through WAVE regulatory complex (WRC)-mediated postsynaptic actin reorganization. The disruption of DNlg1, DNlg2, or their presynaptic partner neurexin (DNrx) led to a dramatic decrease in the amount of F-actin. Further study showed that DNlg1, but not DNlg2 or DNlg3, directly interacts with the WRC via its C-terminal interacting receptor sequence. That interaction is required to recruit WRC to the postsynaptic membrane to promote F-actin assembly. Furthermore, the interaction between DNlg1 and the WRC is essential for DNlg1 to rescue the morphological and electrophysiological defects in dnlg1 mutants. Our results reveal a novel mechanism by which the DNrx-DNlg1 trans-synaptic interaction coordinates structural and functional properties at the neuromuscular junction.


Assuntos
Actinas/genética , Moléculas de Adesão Celular Neuronais/genética , Glicoproteínas/genética , Complexos Multiproteicos/genética , Neuropeptídeos/genética , Actinas/química , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/química , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Glicoproteínas/química , Proteínas de Membrana/química , Proteínas de Membrana/genética , Complexos Multiproteicos/química , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Junção Neuromuscular/genética , Junção Neuromuscular/fisiologia , Neuropeptídeos/química , Terminações Pré-Sinápticas/química , Receptores de Glutamato/genética , Sinapses/genética , Transmissão Sináptica/genética , Família de Proteínas da Síndrome de Wiskott-Aldrich/química , Família de Proteínas da Síndrome de Wiskott-Aldrich/genética
13.
J Biol Chem ; 292(44): 17991-18005, 2017 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-28912273

RESUMO

The neuroligin (Nlg) family of neural cell adhesion molecules is thought to be required for synapse formation and development and has been linked to the development of autism spectrum disorders in humans. In Drosophila melanogaster, mutations in the neuroligin 1-3 genes have been reported to induce synapse developmental defects at neuromuscular junctions (NMJs), but the role of neuroligin 4 (dnlg4) in synapse development has not been determined. Here, we report that the Drosophila neuroligin 4 (DNlg4) is different from DNlg1-3 in that it presynaptically regulates NMJ synapse development. Loss of dnlg4 results in reduced growth of NMJs with fewer synaptic boutons. The morphological defects caused by dnlg4 mutant are associated with a corresponding decrease in synaptic transmission efficacy. All of these defects could only be rescued when DNlg4 was expressed in the presynapse of NMJs. To understand the basis of DNlg4 function, we looked for genetic interactions and found connections with the components of the bone morphogenetic protein (BMP) signaling pathway. Immunostaining and Western blot analyses demonstrated that the regulation of NMJ growth by DNlg4 was due to the positive modulation of BMP signaling by DNlg4. Specifically, BMP type I receptor thickvein (Tkv) abundance was reduced in dnlg4 mutants, and immunoprecipitation assays showed that DNlg4 and Tkv physically interacted in vivo Our study demonstrates that DNlg4 presynaptically regulates neuromuscular synaptic growth via the BMP signaling pathway by modulating Tkv.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Proteínas do Tecido Nervoso/metabolismo , Neurogênese , Junção Neuromuscular/metabolismo , Terminações Pré-Sinápticas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Animais Geneticamente Modificados , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/agonistas , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Proteínas de Drosophila/agonistas , Proteínas de Drosophila/genética , Técnicas de Inativação de Genes , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Mutação , Proteínas do Tecido Nervoso/genética , Junção Neuromuscular/enzimologia , Junção Neuromuscular/ultraestrutura , Terminações Pré-Sinápticas/enzimologia , Terminações Pré-Sinápticas/ultraestrutura , Multimerização Proteica , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Sinapses/enzimologia , Sinapses/metabolismo , Sinapses/ultraestrutura , Transmissão Sináptica
14.
J Biol Chem ; 292(35): 14334-14348, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28710284

RESUMO

Synaptic vesicles (SVs) form distinct pools at synaptic terminals, and this well-regulated separation is necessary for normal neurotransmission. However, how the SV cluster, in particular synaptic compartments, maintains normal neurotransmitter release remains a mystery. The presynaptic protein Neurexin (NRX) plays a significant role in synaptic architecture and function, and some evidence suggests that NRX is associated with neurological disorders, including autism spectrum disorders. However, the role of NRX in SV clustering is unclear. Here, using the neuromuscular junction at the 2-3 instar stages of Drosophila larvae as a model and biochemical imaging and electrophysiology techniques, we demonstrate that Drosophila NRX (DNRX) plays critical roles in regulating synaptic terminal clustering and release of SVs. We found that DNRX controls the terminal clustering and release of SVs by stimulating presynaptic F-actin. Furthermore, our results indicate that DNRX functions through the scaffold protein Scribble and the GEF protein DPix to activate the small GTPase Ras-related C3 Botulinum toxin substrate 1 (Rac1). We observed a direct interaction between the C-terminal PDZ-binding motif of DNRX and the PDZ domains of Scribble and that Scribble bridges DNRX to DPix, forming a DNRX-Scribble-DPix complex that activates Rac1 and subsequently stimulates presynaptic F-actin assembly and SV clustering. Taken together, our work provides important insights into the function of DNRX in regulating SV clustering, which could help inform further research into pathological neurexin-mediated mechanisms in neurological disorders such as autism.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Citoesqueleto de Actina/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Membrana/metabolismo , Junção Neuromuscular/metabolismo , Vesículas Sinápticas/metabolismo , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Animais Geneticamente Modificados , Moléculas de Adesão Celular Neuronais/química , Moléculas de Adesão Celular Neuronais/genética , Proteínas de Drosophila/agonistas , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Fenômenos Eletrofisiológicos , Deleção de Genes , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Larva/citologia , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Junção Neuromuscular/citologia , Junção Neuromuscular/crescimento & desenvolvimento , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Proteínas rac de Ligação ao GTP/agonistas , Proteínas rac de Ligação ao GTP/química , Proteínas rac de Ligação ao GTP/metabolismo
15.
J Mol Cell Biol ; 9(3): 231-242, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28498949

RESUMO

Neuroligins (Nlgs) are transmembrane cell adhesion molecules playing essential roles in synapse development and function. Genetic mutations in neuroligin genes have been linked with some neurodevelopmental disorders such as autism. These mutated Nlgs are mostly retained in the endoplasmic reticulum (ER). However, the mechanisms underlying normal Nlg maturation and trafficking have remained largely unknown. Here, we found that Drosophila neuroligin 2 (DNlg2) undergoes proteolytic cleavage in the ER in a variety of Drosophila tissues throughout developmental stages. A region encompassing Y642-T698 is required for this process. The immature non-cleavable DNlg2 is retained in the ER and non-functional. The C-terminal fragment of DNlg2 instead of the full-length or non-cleavable DNlg2 is able to rescue neuromuscular junction defects and GluRIIB reduction induced by dnlg2 deletion. Intriguingly, the autism-associated R598C mutation in DNlg2 leads to similar marked defects in DNlg2 proteolytic process and ER export, revealing a potential role of the improper Nlg cleavage in autism pathogenesis. Collectively, our findings uncover a specific mechanism that controls DNlg2 maturation and trafficking via proteolytic cleavage in the ER, suggesting that the perturbed proteolytic cleavage of Nlgs likely contributes to autism disorder.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas de Drosophila/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Animais Geneticamente Modificados , Transtorno Autístico/genética , Moléculas de Adesão Celular Neuronais/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Humanos , Mutação , Proteínas do Tecido Nervoso/genética , Junção Neuromuscular/metabolismo , Transporte Proteico
16.
Front Mol Neurosci ; 10: 57, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28326013

RESUMO

Neuronal activity mediated by voltage-gated channels provides the basis for higher-order behavioral tasks that orchestrate life. Chaperone-mediated regulation, one of the major means to control protein quality and function, is an essential route for controlling channel activity. Here we present evidence that Drosophila ER chaperone Calnexin colocalizes and interacts with the α subunit of sodium channel Paralytic. Co-immunoprecipitation analysis indicates that Calnexin interacts with Paralytic protein variants that contain glycosylation sites Asn313, 325, 343, 1463, and 1482. Downregulation of Calnexin expression results in a decrease in Paralytic protein levels, whereas overexpression of the Calnexin C-terminal calcium-binding domain triggers an increase reversely. Genetic analysis using adult climbing, seizure-induced paralysis, and neuromuscular junction indicates that lack of Calnexin expression enhances Paralytic-mediated locomotor deficits, suppresses Paralytic-mediated ghost bouton formation, and regulates minature excitatory junction potentials (mEJP) frequency and latency time. Taken together, our findings demonstrate a need for chaperone-mediated regulation on channel activity during locomotor control, providing the molecular basis for channlopathies such as epilepsy.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...