FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2085404787> ?p ?o ?g. }

• W2085404787 endingPage "6" @default.
• W2085404787 startingPage "5" @default.
• W2085404787 abstract "Hot off the Press30 November 2012free access Chaperoning the synapse—NMNAT protects Bruchpilot from crashing Elsa Lauwers Elsa Lauwers KU Leuven Department of Human Genetics and Leuven research Institute for Neuroscience and Disease, VIB Center for the Biology of Disease, Leuven, Belgium Search for more papers by this author Patrik Verstreken Patrik Verstreken KU Leuven Department of Human Genetics and Leuven research Institute for Neuroscience and Disease, VIB Center for the Biology of Disease, Leuven, Belgium Search for more papers by this author Elsa Lauwers Elsa Lauwers KU Leuven Department of Human Genetics and Leuven research Institute for Neuroscience and Disease, VIB Center for the Biology of Disease, Leuven, Belgium Search for more papers by this author Patrik Verstreken Patrik Verstreken KU Leuven Department of Human Genetics and Leuven research Institute for Neuroscience and Disease, VIB Center for the Biology of Disease, Leuven, Belgium Search for more papers by this author Author Information Elsa Lauwers1 and Patrik Verstreken1 1KU Leuven Department of Human Genetics and Leuven research Institute for Neuroscience and Disease, VIB Center for the Biology of Disease, Leuven, Belgium EMBO Reports (2013)14:5-6https://doi.org/10.1038/embor.2012.193 There is a Scientific Report (January 2013) associated with this Hot off the Press. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Synapses perform several tasks independently from the cell body of the neuron, including synaptic vesicle recycling through endocytosis or local protein maturation and degradation. Failure to regulate protein function locally is detrimental to the nervous system as evidenced by neuronal dysfunctions that arise as a consequence of synaptic ageing. This relative synaptic autonomy comes with a need for mechanisms that ensure correct protein (re)folding, and there is accumulating evidence that key chap-erones have a central role in the regulation and maintenance of synaptic structural integrity and function [1]. Work by Grace Zhai's group, published in this issue of EMBO reports, demonstrates a key role of the Drosophila nicotinamide mononucleotide adenylyltransferase (NMNAT) chaperone in the protection of active zone components against activity-induced degeneration (Fig 1; [2]). Figure 1.Results reported by Zang and colleagues [2] reveal a specific role of nicotinamide mononucleotide adenylyltransferase (NMNAT) in preserving active zone structure against use-dependent decline. This protection is exerted by direct interaction with BRP and protection of this key structural protein against ubiquitination and subsequent degradation. BRP, Bruchpilot; Ub, ubiquitin. Download figure Download PowerPoint Active zones, the specialized sites for neurotransmitter release at presynaptic terminals, are characterized by a dense protein network called the cytomatrix at the active zone (CAZ). The protein machinery of the CAZ is responsible for efficient synaptic vesicle tethering, docking and fusion with the presynaptic membrane and, thus, for reliable signal transmission from the neuron to the postsynaptic cell. Clearly, proteins in the CAZ are tightly regulated, especially in response to external cues such as synaptic activity [3,4]. Yet, this particularly crowded protein environment might be favourable for the formation of non-functional—and sometimes toxic—protein aggregates. Chaperones that act at the synapse reduce the probability of crucial protein aggregation by preventing and reverting these inappropriate interactions, which happen as a result of environmental stress. One of these chaperones, the Drosophila neuroprotective NMNAT, was identified in a genetic screen for factors involved in synapse function [5]. Its chaperone activity was later confirmed by using in vitro and in vivo protein folding assays [6]. NMNAT null mutants show severe and early onset neurodegeneration, whereas neurodevelopment does not seem to be strongly affected. Interestingly, degeneration of photoreceptors lacking NMNAT can be significantly attenuated by limiting synaptic activity, either by rearing flies in the dark or by introducing the no receptor potential A (norpA) mutation that blocks phototransduction [5]. These results indicate that NMNAT protects adult neurons from activity-induced degeneration. In this issue of EMBO reports, Zang and colleagues report a role for NMNAT at the synapse. They observed that loss or reduced levels of NMNAT leads to a concomitant loss of several synaptic markers including cysteine-string protein (CSP), synaptotagmin and the active zone structural protein Bruchpilot (BRP). Remarkably, BRP was the only one of these proteins found to co-immunoprecipitate with NMNAT from brain lysates. Both proteins show approximately 50% co-localization at the neuromuscular junction when imaged by 3D-SIM™ super-resolution microscopy, suggesting that NMNAT might act directly as a chaperone for maintaining a functional BRP conformation. Consistent with a protective role of NMNAT against BRP degradation, RNA interference-mediated NMNAT knockdown leads to BRP ubiquitination, whereas this modification was not detected in control brain lysates. Given the involvement of the ubiquitin proteasome pathway in regulating synaptic development and function [1], the authors tested the effect of the proteasome inhibitor MG-132 on BRP ubiquitination. They observed an increased level of BRP ubiquitination in wild-type flies fed with this drug, suggesting a role for the proteasome in the clearance of ubiquitinated BRP. By contrast, overexpression of NMNAT reduces the level of BRP ubiquitination both in the absence and the presence of MG-132, providing further evidence for the protective role of this chaperone against ubiquitination of BRP (Fig 1). a key role of the […] nicotinamide mononucleotide adenylyltransferase (NMNAT) chaperone in the protection of active zone components against activity-induced degeneration BRP is a cytoskeletal-like protein that is an integral component of T-bars—electron-dense structures that project from the presynaptic membrane and around which synaptic vesicles cluster. In agreement with a protective role of NMNAT against BRP ubiquitination, reduced levels of this chaperone give rise to a marked decrease in T-bar size in an age-dependent manner (Fig 1). Active zones are known to show dynamic changes in response to synaptic activity, and NMNAT was previously reported to protect photoreceptors against activity-induced degeneration [5]. The authors thus tested the effect of minimizing photoreceptor activity on active zone structure by keeping flies in the dark or inhibiting phototransduction by means of the norpA mutation. Both manipulations largely reversed the effect of NMNAT knockdown on T-bar size. Absence of light exposure also significantly reduced the amount of BRP that co-immunoprecipitates with NMNAT, indicating that neuronal activity regulates NMNAT–BRP interaction. Further experiments are needed to examine whether there is a positive correlation between synaptic activity and BRP ubiquitination levels, and whether NMNAT can indeed keep T-bar structure intact by protecting BRP against this modification under conditions of high synaptic activity. Finally, the study shows that reduced NMNAT levels not only caused a loss of BRP from the synapse but also a specific mislocalization of this protein to the cell body, where it accumulates in clusters together with the remaining NMNAT protein. Under these conditions BRP co-immunoprecipitated with the stress-induced Hsp70, a chaperone classically used as a marker for protein aggregation. It is still unclear whether these BRP clusters form as a result of defective anterograde trafficking and/or of enhanced retrograde transport of BRP. In the absence of light stimulation T-bars are properly assembled in nmnat null photoreceptors, but at this stage a role of NMNAT in regulating the axonal transport of BRP under conditions of normal synaptic activity cannot be excluded. Noticeably, two independent recent reports show involvement of NMNAT in mitochondrial mobility [7,8]. As BRP and NMNAT co-localize and interact with one another, the simplest model that accounts for all the observations by Zang et al is that NMNAT directly prevents activity-induced ubiquitination of BRP and subsequent degradation. Yet, as its name indicates, this chaperone is an essential enzyme in NAD synthesis. It was previously shown by the Bellen lab that mutant versions of NMNAT, impaired for NAD production, rescue photoreceptor degeneration caused by loss of NMNAT [5]. This strongly suggests that NAD production is not required for stabilization of BRP but this might need further scrutiny [9]. …reduced levels of this chaperone [NMNAT] give rise to a marked decrease in T-bar size While providing further insights into the role of NMNAT at the active zone in Drosophila, the paper by Zang et al might also have important implications for neurodegeneration in mammals. When ectopically expressed in mice, Nmnat has a protective role against Wallerian degeneration, that is, synapse and axon degeneration that rapidly occurs distal from an axonal wound in wild-type animals. This process is significantly delayed in mice overexpressing a chimaeric protein consisting of the amino-terminal 70 residues of the ubiquitination factor E4B (Ube4b) fused through a linker to Nmnat1, known as the Wallerian degeneration slow (Wlds) protein. Conversely, mutations in the human NMNAT1 gene were characterized in several families with Leber congenital amaurosis—a severe, early-onset neurodegenerative disease of the retina [10,11,12,13]. As Wlds or Nmnat1 overexpression protects axons from degeneration in various disease models [9], Nmnat1 emerges as a promising candidate for developing protective strategies against axonal degeneration in peripheral neuropathies such as amyotrophic lateral sclerosis but also in glaucoma, AIDS and other diseases [9]. Conflict of Interest The authors declare that they have no conflict of interest. Biography Elsa Lauwers and Patrik Verstreken are at the KU Leuven Department of Human Genetics and Leuven research Institute for Neuroscience and Disease, VIB Center for the Biology of Disease, Leuven, Belgium. E-mail: [email protected] References Wyttenbach A, O'Connor V (2011) Folding for the Synapse. SpringerCrossrefWeb of Science®Google Scholar Zang S et al (2012) EMBO Rep (in the press)Google Scholar Miśkiewicz K et al (2011) Neuron 72: 776–788Web of Science®Google Scholar Peled ES, Isacoff EY (2011) Nat Neurosci 14: 519–526Web of Science®Google Scholar Zhai RG et al (2006) PLoS Biol 4: e416Google Scholar Zhai RG et al (2008) Nature 452: 887–891Web of Science®Google Scholar Fang Y et al (2012) Curr Biol 22: 590–595Web of Science®Google Scholar Avery M et al (2012) Curr Biol 22: 596–600Web of Science®Google Scholar Feng Y et al (2010) Protein Cell 1: 237–245Web of Science®Google Scholar Koenekoop RK et al (2012) Nat Genet 44: 1035–1039Web of Science®Google Scholar Falk MJ et al (2012) Nat Genet 44: 1040–1045Web of Science®Google Scholar Perrault I et al (2012) Nat Genet 44: 975–977Web of Science®Google Scholar Chiang PW et al (2012) Nat Genet 44: 972–974Web of Science®Google Scholar Previous ArticleNext Article Volume 14Issue 11 January 2013In this issue FiguresReferencesRelatedDetailsLoading ..." @default.
• W2085404787 created "2016-06-24" @default.
• W2085404787 creator A5040983698 @default.
• W2085404787 creator A5089999732 @default.
• W2085404787 date "2012-11-30" @default.
• W2085404787 modified "2023-10-12" @default.
• W2085404787 title "Chaperoning the synapse—NMNAT protects Bruchpilot from crashing" @default.
• W2085404787 cites W4238961125 @default.
• W2085404787 doi "https://doi.org/10.1038/embor.2012.193" @default.
• W2085404787 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3537146" @default.
• W2085404787 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23196365" @default.
• W2085404787 hasPublicationYear "2012" @default.
• W2085404787 type Work @default.
• W2085404787 sameAs 2085404787 @default.
• W2085404787 citedByCount "3" @default.
• W2085404787 countsByYear W20854047872013 @default.
• W2085404787 countsByYear W20854047872017 @default.
• W2085404787 countsByYear W20854047872022 @default.
• W2085404787 crossrefType "journal-article" @default.
• W2085404787 hasAuthorship W2085404787A5040983698 @default.
• W2085404787 hasAuthorship W2085404787A5089999732 @default.
• W2085404787 hasBestOaLocation W20854047872 @default.
• W2085404787 hasConcept C70721500 @default.
• W2085404787 hasConcept C86803240 @default.
• W2085404787 hasConcept C95444343 @default.
• W2085404787 hasConceptScore W2085404787C70721500 @default.
• W2085404787 hasConceptScore W2085404787C86803240 @default.
• W2085404787 hasConceptScore W2085404787C95444343 @default.
• W2085404787 hasIssue "1" @default.
• W2085404787 hasLocation W20854047871 @default.
• W2085404787 hasLocation W20854047872 @default.
• W2085404787 hasLocation W20854047873 @default.
• W2085404787 hasLocation W20854047874 @default.
• W2085404787 hasOpenAccess W2085404787 @default.
• W2085404787 hasPrimaryLocation W20854047871 @default.
• W2085404787 hasRelatedWork W1641042124 @default.
• W2085404787 hasRelatedWork W1990804418 @default.
• W2085404787 hasRelatedWork W1993764875 @default.
• W2085404787 hasRelatedWork W2013243191 @default.
• W2085404787 hasRelatedWork W2046158694 @default.
• W2085404787 hasRelatedWork W2082860237 @default.
• W2085404787 hasRelatedWork W2117258802 @default.
• W2085404787 hasRelatedWork W2130076355 @default.
• W2085404787 hasRelatedWork W2151865869 @default.
• W2085404787 hasRelatedWork W4234157524 @default.
• W2085404787 hasVolume "14" @default.
• W2085404787 isParatext "false" @default.
• W2085404787 isRetracted "false" @default.
• W2085404787 magId "2085404787" @default.
• W2085404787 workType "article" @default.