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Guangyan Miao, Yan G Zhao, Hongyu Zhao, Cuicui Ji, Huayu Sun, Yingyu Chen, Hong Zhang
Autophagy helps to maintain cellular homeostasis by removing misfolded proteins and damaged organelles, and generally acts as a cytoprotective mechanism for neuronal survival. Here we showed that mice deficient in the Vici syndrome gene Epg5, which is required for autophagosome maturation, show accumulation of ubiquitin-positive inclusions and SQSTM1 aggregates in various retinal cell types. In epg5(-/-) retinas, photoreceptor function is greatly impaired, and degenerative features including progressively reduced numbers of photoreceptor cells and increased numbers of apoptotic cells in the outer nuclear layer are observed, while the morphology of other parts of the retina is not severely affected...
October 7, 2016: Autophagy
Zheng Wang, Guangyan Miao, Xue Xue, Xiangyang Guo, Chongzhen Yuan, Zhaoyu Wang, Gangming Zhang, Yingyu Chen, Du Feng, Junjie Hu, Hong Zhang
Mutations in the human autophagy gene EPG5 cause the multisystem disorder Vici syndrome. Here we demonstrated that EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. EPG5 is recruited to late endosomes/lysosomes by direct interaction with Rab7 and the late endosomal/lysosomal R-SNARE VAMP7/8. EPG5 also binds to LC3/LGG-1 (mammalian and C. elegans Atg8 homolog, respectively) and to assembled STX17-SNAP29 Qabc SNARE complexes on autophagosomes. EPG5 stabilizes and facilitates the assembly of STX17-SNAP29-VAMP7/8 trans-SNARE complexes, and promotes STX17-SNAP29-VAMP7-mediated fusion of reconstituted proteoliposomes...
September 1, 2016: Molecular Cell
Ke-Sheng Wang, Xuefeng Liu, Changchun Xie, Ying Liu, Chun Xu
Non-parametric methods such as Wilcoxon test have the advantages of no assumptions for the underlying survival distributions. Alzheimer's disease (AD) is a chronic neurodegenerative disease while the ectopic P-granules autophagy protein 5 homolog (EPG5 gene) is highly expressed in human brain and may implicate in the pathogenesis of neurodegenerative disorders. The present study explored the associations of 26 single-nucleotide polymorphisms (SNPs) in the EPG5 gene with the age at onset (AAO) of AD using a family-based association test (FBAT)-Wilcoxon statistic in a family-based study...
September 1, 2016: Journal of Molecular Neuroscience: MN
Susan Byrne, Carlo Dionisi-Vici, Luke Smith, Mathias Gautel, Heinz Jungbluth
Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys...
2016: Orphanet Journal of Rare Diseases
Susan Byrne, Lara Jansen, Jean-Marie U-King-Im, Ata Siddiqui, Hart G W Lidov, Istvan Bodi, Luke Smith, Rachael Mein, Thomas Cullup, Carlo Dionisi-Vici, Lihadh Al-Gazali, Mohammed Al-Owain, Zandre Bruwer, Khalid Al Thihli, Rana El-Garhy, Kevin M Flanigan, Kandamurugu Manickam, Erik Zmuda, Wesley Banks, Ruth Gershoni-Baruch, Hanna Mandel, Efrat Dagan, Annick Raas-Rothschild, Hila Barash, Francis Filloux, Donnell Creel, Michael Harris, Ada Hamosh, Stefan Kölker, Darius Ebrahimi-Fakhari, Georg F Hoffmann, David Manchester, Philip J Boyer, Adnan Y Manzur, Charles Marques Lourenco, Daniela T Pilz, Arveen Kamath, Prab Prabhakar, Vamshi K Rao, R Curtis Rogers, Monique M Ryan, Natasha J Brown, Catriona A McLean, Edith Said, Ulrike Schara, Anja Stein, Caroline Sewry, Laura Travan, Frits A Wijburg, Martin Zenker, Shehla Mohammed, Manolis Fanto, Mathias Gautel, Heinz Jungbluth
Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p...
March 2016: Brain: a Journal of Neurology
Qun Lu, Christine C Yokoyama, Jesse W Williams, Megan T Baldridge, Xiaohua Jin, Brittany DesRochers, Traci Bricker, Craig B Wilen, Juhi Bagaitkar, Ekaterina Loginicheva, Alexey Sergushichev, Darren Kreamalmeyer, Brian C Keller, Yan Zhao, Amal Kambal, Douglas R Green, Jennifer Martinez, Mary C Dinauer, Michael J Holtzman, Erika C Crouch, Wandy Beatty, Adrianus C M Boon, Hong Zhang, Gwendalyn J Randolph, Maxim N Artyomov, Herbert W Virgin
Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found that Epg5-deficient mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages...
January 13, 2016: Cell Host & Microbe
Darius Ebrahimi-Fakhari, Afshin Saffari, Lara Wahlster, Jenny Lu, Susan Byrne, Georg F Hoffmann, Heinz Jungbluth, Mustafa Sahin
Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions...
February 2016: Brain: a Journal of Neurology
Amaury Herpin, Eva Englberger, Mario Zehner, Robin Wacker, Manfred Gessler, Manfred Schartl
Autophagy is an evolutionarily conserved catabolic process that transports cytoplasmic components to lysosomes for degradation. In addition to the canonical view of strict stress-response-induced autophagy, selectively programmed autophagy was recently reported in the context of gonad development of flies and worms, where autophagy seems to be necessary for clearance of germ plasm components. Similar functions have not been described in vertebrates. We used the medaka fish to study the role of autophagy in gonad formation and gametogenesis for the first time in a vertebrate organism for which the germ line is specified by germ plasm...
October 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Nadja Ehmke, Nima Parvaneh, Peter Krawitz, Mahmoud-Reza Ashrafi, Parviz Karimi, Mehrzad Mehdizadeh, Ulrike Krüger, Jochen Hecht, Stefan Mundlos, Peter N Robinson
Vici syndrome is a rare autosomal recessively inherited multisystem disorder characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, psychomotor delay, and hypopigmentation. Cullup et al. recently identified mutations in the gene EPG5 as the cause of Vici syndrome. EPG5 is involved in autophagy, an evolutionarily conserved lysosomal degradation process that is essential for cell homeostasis. Following the first description in 1988 by Vici et al., 24 other cases of Vici syndrome have been published with variable expression of the defining features...
December 2014: American Journal of Medical Genetics. Part A
Yan G Zhao, Hongyu Zhao, Huayu Sun, Hong Zhang
Autophagy activity is essential for the survival of neural cells. Impairment of autophagy has been implicated in the pathogenesis of neurodegenerative disorders. Unlike the massive neuron loss in mice deficient for autophagy genes essential for autophagosome formation, we demonstrated that mice deficient for the metazoan-specific autophagy gene Epg5 develop selective neuronal damage and exhibit key characteristics of amyotrophic lateral sclerosis. Epg5 deficiency blocks the maturation of autophagosomes into degradative autolysosomes, slows endocytic degradation and also impairs endocytic recycling...
August 2013: Autophagy
Hongyu Zhao, Yan G Zhao, Xingwei Wang, Lanjun Xu, Lin Miao, Du Feng, Quan Chen, Attila L Kovács, Dongsheng Fan, Hong Zhang
The molecular mechanism underlying the selective vulnerability of certain neuronal populations associated with neurodegenerative diseases remains poorly understood. Basal autophagy is important for maintaining axonal homeostasis and preventing neurodegeneration. In this paper, we demonstrate that mice deficient in the metazoan-specific autophagy gene Epg5/epg-5 exhibit selective damage of cortical layer 5 pyramidal neurons and spinal cord motor neurons. Pathologically, Epg5 knockout mice suffered muscle denervation, myofiber atrophy, late-onset progressive hindquarter paralysis, and dramatically reduced survival, recapitulating key features of amyotrophic lateral sclerosis (ALS)...
March 18, 2013: Journal of Cell Biology
Thomas Cullup, Ay Lin Kho, Carlo Dionisi-Vici, Birgit Brandmeier, Frances Smith, Zoe Urry, Michael A Simpson, Shu Yau, Enrico Bertini, Verity McClelland, Mohammed Al-Owain, Stefan Koelker, Christian Koerner, Georg F Hoffmann, Frits A Wijburg, Amber E ten Hoedt, R Curtis Rogers, David Manchester, Rie Miyata, Masaharu Hayashi, Elizabeth Said, Doriette Soler, Peter M Kroisel, Christian Windpassinger, Francis M Filloux, Salwa Al-Kaabi, Jozef Hertecant, Miguel Del Campo, Stefan Buk, Istvan Bodi, Hans-Hilmar Goebel, Caroline A Sewry, Stephen Abbs, Shehla Mohammed, Dragana Josifova, Mathias Gautel, Heinz Jungbluth
Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes...
January 2013: Nature Genetics
Eugenia Morán-Diez, Rosa Hermosa, Patrizia Ambrosino, Rosa E Cardoza, Santiago Gutiérrez, Matteo Lorito, Enrique Monte
Considering the complexity of the in vivo interactions established by a mycoparasitic biocontrol agent at the plant rhizosphere, proteomic, genomic, and transcriptomic approaches were used to study a novel Trichoderma gene coding for a plant cell wall (PCW)-degrading enzyme. A proteome analysis, using a three-component (Trichoderma spp.-tomato plantlets-pathogen) system, allowed us to identify a differentially expressed Trichoderma harzianum endopolygalacturonase (endoPG). Spot 0303 remarkably increased only in the presence of the soilborne pathogens Rhizoctonia solani and Pythium ultimum, and corresponded to an expressed sequence tag from a T...
August 2009: Molecular Plant-microbe Interactions: MPMI
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