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https://www.readbyqxmd.com/read/28399880/quantitative-proteomic-analysis-of-parkin-substrates-in-drosophila-neurons
#1
Aitor Martinez, Benoit Lectez, Juanma Ramirez, Oliver Popp, James D Sutherland, Sylvie Urbé, Gunnar Dittmar, Michael J Clague, Ugo Mayor
BACKGROUND: Parkin (PARK2) is an E3 ubiquitin ligase that is commonly mutated in Familial Parkinson's Disease (PD). In cell culture models, Parkin is recruited to acutely depolarised mitochondria by PINK1. PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy. Many substrates have been identified using cell culture models in combination with depolarising drugs or proteasome inhibitors, but not in more physiological settings...
April 11, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28384478/the-retromer-supports-ampa-receptor-trafficking-during-ltp
#2
Paul Temkin, Wade Morishita, Debanjan Goswami, Kristin Arendt, Lu Chen, Robert Malenka
Alterations in the function of the retromer, a multisubunit protein complex that plays a specialized role in endosomal sorting, have been linked to Alzheimer's and Parkinson's diseases, yet little is known about the retromer's role in the mature brain. Using in vivo knockdown of the critical retromer component VPS35, we demonstrate a specific role for this endosomal sorting complex in the trafficking of AMPA receptors during NMDA-receptor-dependent LTP at mature hippocampal synapses. The impairment of LTP due to VPS35 knockdown was mechanistically independent of any role of the retromer in the production of Aβ from APP...
April 5, 2017: Neuron
https://www.readbyqxmd.com/read/28383562/vps35-regulates-parkin-substrate-aimp2-toxicity-by-facilitating-lysosomal-clearance-of-aimp2
#3
Seung Pil Yun, Hyojung Kim, Sangwoo Ham, Seung-Hwan Kwon, Gum Hwa Lee, Joo-Ho Shin, Sang Hun Lee, Han Seok Ko, Yunjong Lee
Vacuolar protein sorting-associated protein 35 (VPS35) is involved in retrograde transport of proteins from endosomes to trans-Golgi network. Gene mutations in VPS35 are linked to autosomal dominant late-onset Parkinson's disease (PD). Although the identification of VPS35 mutations has provided novel insight about its interactions with several PD-associated genes including leucine-rich repeat kinase 2 (LRRK2) and α-synuclein, little information is available about the molecular mechanisms of cell death downstream of VPS35 dysfunction...
April 6, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28341739/modifiers-of-prion-protein-biogenesis-and-recycling-identified-by-a-highly-parallel-endocytosis-kinetics-assay
#4
Boris A Ballmer, Rita Moos, Prisca Liberali, Lucas Pelkmans, Simone Hornemann, Adriano Aguzzi
The cellular prion protein, PrP(C), is attached by a glycosylphosphatidylinositol anchor to the outer leaflet of the plasma membrane. Its misfolded isoform PrP(Sc) is the causative agent of prion diseases. Conversion of PrP(C) into PrP(Sc) is thought to take place at the cell surface or in endo-lysosomal organelles. Understanding the intracellular trafficking of PrP(C) may therefore help elucidating the conversion process. Here we describe a time-resolved fluorescence resonance energy transfer (FRET) assay reporting membrane expression and real-time internalization rates of PrP(C) The assay is suitable for high-throughput genetic and pharmaceutical screens for modulators of PrP(C) trafficking...
March 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28289797/-epidemiology-and-causes-of-parkinson-s-disease
#5
C M Lill, C Klein
Parkinson's disease (PD) is the second most common neurodegenerative disease and has a growing socioeconomic impact due to demographic changes in the industrial nations. There are several forms of PD, a fraction of which (<5%) are monogenic, i. e. caused by mutations in single genes. At present, six genes have been established for the clinically classical form of parkinsonism including three autosomal dominantly (SNCA, LRRK2, VPS35) and three autosomal recessively inherited ones (Parkin, PINK1, DJ-1)...
April 2017: Der Nervenarzt
https://www.readbyqxmd.com/read/28222538/vps35-the-retromer-complex-and-parkinson-s-disease
#6
Erin T Williams, Xi Chen, Darren J Moore
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies...
February 8, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28179995/caspase-mediated-proteolysis-of-the-sorting-nexin-2-disrupts-retromer-assembly-and-potentiates-met-hepatocyte-growth-factor-receptor-signaling
#7
Catherine M Duclos, Audrey Champagne, Julie C Carrier, Caroline Saucier, Christine L Lavoie, Jean-Bernard Denault
The unfolding of apoptosis involves the cleavage of hundreds of proteins by the caspase family of cysteinyl peptidases. Among those substrates are proteins involved in intracellular vesicle trafficking with a net outcome of shutting down the crucial processes governing protein transport to organelles and to the plasma membrane. However, because of the intertwining of receptor trafficking and signaling, cleavage of specific proteins may lead to unintended consequences. Here we show that in apoptosis, sorting nexin 1 and 2 (SNX1 and SNX2), two proteins involved in endosomal sorting, are cleaved by initiator caspases and also by executioner caspase-6 in the case of SNX2...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28173004/impaired-striatal-dopamine-release-in-homozygous-vps35-d620n-knock-in-mice
#8
Nobutaka Ishizu, Daishi Yui, Akira Hebisawa, Hidenori Aizawa, Wanpeng Cui, Yuko Fujita, Kenji Hashimoto, Itsuki Ajioka, Hidehiro Mizusawa, Takanori Yokota, Kei Watase
No abstract text is available yet for this article.
October 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28131822/genome-scale-networks-link-neurodegenerative-disease-genes-to-%C3%AE-synuclein-through-specific-molecular-pathways
#9
Vikram Khurana, Jian Peng, Chee Yeun Chung, Pavan K Auluck, Saranna Fanning, Daniel F Tardiff, Theresa Bartels, Martina Koeva, Stephen W Eichhorn, Hadar Benyamini, Yali Lou, Andy Nutter-Upham, Valeriya Baru, Yelena Freyzon, Nurcan Tuncbag, Michael Costanzo, Bryan-Joseph San Luis, David C Schöndorf, M Inmaculada Barrasa, Sepehr Ehsani, Neville Sanjana, Quan Zhong, Thomas Gasser, David P Bartel, Marc Vidal, Michela Deleidi, Charles Boone, Ernest Fraenkel, Bonnie Berger, Susan Lindquist
Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson's disease. Genome-wide screens in yeast identified 332 genes that impact α-syn toxicity. To "humanize" this molecular network, we developed a computational method, TransposeNet. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure, and interaction topology...
February 22, 2017: Cell Systems
https://www.readbyqxmd.com/read/28129035/where-no-ras-has-gone-before-vps35-steers-n-ras-through-the-cytosol
#10
Mo Zhou, Mark R Philips
Ras is the best-studied member of the superfamily of small GTPases because of its role in cancer. Ras proteins transmit signals for proliferation, differentiation and survival. Three RAS genes encode 4 isoforms. All Ras isoforms have long been considered membrane bound, a localization required for function. Our recent study revealed that N-Ras differs from all other isoforms in being largely cytosolic even following modification with a prenyl lipid. Endogenous, cytosolic N-Ras chromatographed in both high and low molecular weight pools, a pattern that required prenylation, suggesting prenyl-dependent interaction with other proteins...
January 27, 2017: Small GTPases
https://www.readbyqxmd.com/read/28110103/the-retromer-complex-system-in-a-transgenic-mouse-model-of-ad-influence-of-age
#11
Jin Chu, Domenico Praticò
Deficiencies of the retrograde transport mediated by the retromer complex have been described in Alzheimer's disease (AD). Genetic manipulation of retromer modulates brain amyloidosis in Tg2576 mice. However, whether the complex is altered during the development of the AD-like phenotype remains unknown. In this study we assayed the expression levels of the vacuolar sorting protein 35 (VPS35), VPS26, VPS29, and its cargo proteins, cation independent mannose 6-phosphate receptor, sortilin-related receptor in brains of Tg2576 and controls at the ages of 3, 8, and 14 months...
January 3, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28040727/a-conserved-retromer-sorting-motif-is-essential-for-mitochondrial-dlp1-recycling-by-vps35-in-parkinson-s-disease-model
#12
Wenzhang Wang, Xiaopin Ma, Leping Zhou, Jun Liu, Xiongwei Zhu
Impaired mitochondria dynamics and quality control are involved in mitochondrial dysfunction and pathogenesis of Parkinson's disease (PD). VPS35 mutations cause autosomal dominant PD and we recently demonstrated that fPD-associated VPS35 mutants can cause mitochondrial fragmentation through enhanced VPS35-DLP1 interaction. In this study, we focused on the specific sites on DLP1 responsible for the VPS35-DLP1 interaction. A highly conserved FLV motif was identified in the C-terminus of DLP1, mutation of which significantly reduced VPS35-DLP1 interaction...
February 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/27964832/role-of-the-vps35-d620n-mutation-in-parkinson-s-disease
#13
REVIEW
Megha Mohan, George D Mellick
Parkinson's disease (PD) is a neurodegenerative disorder involving the loss of dopaminergic neurons in the brain. Following the discovery of the PD-causing D620N mutation in the VPS35 (Vacuolar sorting protein 35) gene, dysfunction in the subcellular retromer complex has been strongly implicated in pathogenesis of PD. Although the function and dysfunction of the retromer has been a focus of study for some time, the role of this complex in the development of PD is not fully understood. Investigating cellular alterations that occur when the retromer is rendered dysfunctional, such as when the D620N disease-causing mutation is introduced into various model systems, shows that endosomal processing defects are major contributors to the disease phenotype...
March 2017: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/27932943/vacuolar-protein-sorting-genes-in-parkinson-s-disease-a-re-appraisal-of-mutations-detection-rate-and-neurobiology-of-disease
#14
REVIEW
Stefano Gambardella, Francesca Biagioni, Rosangela Ferese, Carla L Busceti, Alessandro Frati, Giuseppe Novelli, Stefano Ruggieri, Francesco Fornai
Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27924069/retrograde-trafficking-of-vmat2-and-its-role-in-protein-stability-in-non-neuronal-cells
#15
Qiuzi Wu, Hongfei Xu, Wei Wang, Fei Chang, Yu Jiang, Yongjian Liu
Increasing evidence suggests that the impaired neuroprotection of vesicular monoamine transporter 2 (VMAT2) contributes to the pathogenesis of Parkinson's disease. That has been linked to aberrant subcellular retrograde trafficking as strongly indicated by recent genomic studies on familial Parkinson's diseases. However, whether VMAT2 function is regulated by retrograde trafficking is unknown. By using biochemistry and cell biology approaches, we have shown that VMAT2 was stringently localized to the trans-Golgi network and underwent retrograde trafficking in non-neuronal cells...
November 2016: Journal of Biomedical Research
https://www.readbyqxmd.com/read/27917878/spatiotemporal-control-of-interferon-induced-jak-stat-signalling-and-gene-transcription-by-the-retromer-complex
#16
Daniela Chmiest, Nanaocha Sharma, Natacha Zanin, Christine Viaris de Lesegno, Massiullah Shafaq-Zadah, Vonick Sibut, Florent Dingli, Philippe Hupé, Stephan Wilmes, Jacob Piehler, Damarys Loew, Ludger Johannes, Gideon Schreiber, Christophe Lamaze
Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation...
December 5, 2016: Nature Communications
https://www.readbyqxmd.com/read/27909246/retromer-and-wash-dependent-sorting-of-nutrient-transporters-requires-a-multivalent-interaction-network-with-ankrd50
#17
Arunas Kvainickas, Ana Jimenez Orgaz, Heike Nägele, Britta Diedrich, Kate J Heesom, Jörn Dengjel, Peter J Cullen, Florian Steinberg
Retromer and the associated actin-polymerizing WASH complex are essential for the endocytic recycling of a wide range of integral membrane proteins. A hereditary Parkinson's-disease-causing point mutation (D620N) in the retromer subunit VPS35 perturbs retromer's association with the WASH complex and also with the uncharacterized protein ankyrin-repeat-domain-containing protein 50 (ANKRD50). Here, we firmly establish ANKRD50 as a new and essential component of the SNX27-retromer-WASH super complex. Depletion of ANKRD50 in HeLa or U2OS cells phenocopied the loss of endosome-to-cell-surface recycling of multiple transmembrane proteins seen upon suppression of SNX27, retromer or WASH-complex components...
January 15, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/27894086/the-anti-tumor-drug-2-hydroxyoleic-acid-minerval-stimulates-signaling-and-retrograde-transport
#18
Maria L Torgersen, Tove Irene Klokk, Simona Kavaliauskiene, Christian Klose, Kai Simons, Tore Skotland, Kirsten Sandvig
2-hydroxyoleic acid (OHOA, Minerval®) is an example of a substance used for membrane lipid therapy, where the cellular membranes rather than specific proteins constitute the therapeutical target. OHOA is thought to mediate its anti-tumor effect by affecting the biophysical properties of membranes, which leads to altered recruitment and activation of amphitropic proteins, altered cellular signaling, and eventual cell death. Little is known about the initial signaling events upon treatment with OHOA, and whether the altered membrane properties would have any impact on the dynamic intracellular transport system...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27889239/structural-mechanism-for-cargo-recognition-by-the-retromer-complex
#19
María Lucas, David C Gershlick, Ander Vidaurrazaga, Adriana L Rojas, Juan S Bonifacino, Aitor Hierro
Retromer is a multi-protein complex that recycles transmembrane cargo from endosomes to the trans-Golgi network and the plasma membrane. Defects in retromer impair various cellular processes and underlie some forms of Alzheimer's disease and Parkinson's disease. Although retromer was discovered over 15 years ago, the mechanisms for cargo recognition and recruitment to endosomes have remained elusive. Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27872751/novel-gene-tmem230-linked-to-parkinson-s-disease
#20
EDITORIAL
Diana A Olszewska, Conor Fearon, Tim Lynch
Mutations in six genes are known to cause Parkinson's disease (PD) (autosomal dominant: alpha-synuclein, LRRK2, VPS35 and autosomal recessive: Parkin, PINK1 and DJ1) and number of other genes are implicated. In a recent article Deng and colleagues studied a large four generation American family of European descent and linked mutations in a novel gene, transmembrane-protein 230 gene (TMEM230) with lewy body confirmed PD. The authors demonstrated that pathogenic TMEM230 variants in primary mouse neurons affected movement of synaptic vesicles suggesting that TMEM230 may slow vesicular transport...
2016: Journal of Clinical Movement Disorders
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