C. elegans Screen Identifies Autophagy Genes Specific to Multicellular Organisms

Tian, Ye; Li, Zhipeng; Hu, Wanqiu; Ren, Haiyan; Tian, E; Zhao, Yu; Lu, Qun; Huang, Xinxin; Yang, Peiguo; Li, Xin; Wang, Xiaochen; Kovács, Attila; Yu, Li; Zhang, Hong

doi:10.1016/j.cell.2010.04.034

Cited by 370 publications

(556 citation statements)

References 24 publications

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“…31 Epg5 in Caenorhabditis elegans is one of the four eukaryote-specific autophagy genes that regulate different steps of the autophagic pathway in multicellular organisms. 31,33 It is ubiquitously expressed during embryonic development and appears to play an essential role in starvation-induced autophagy. 33 In silico analysis predicts the expression of EPG5 in different mammalian organs, including the central nervous system, skeletal and heart muscle, immune cells, thymus, and others, 34 which are all involved in Vici syndrome.…”

Section: Reviewmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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Pediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. In recent years, studies have revealed a wide spectrum of abnormal cellular functions that include impaired proteolysis, abnormal lipid trafficking, accumulation of lysosomal content, and mitochondrial dysfunction. Within neurons, elaborated degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for maintaining homeostasis and normal cell function. Recent evidence suggests a pivotal role for autophagy in major adult and pediatric neurodegenerative diseases. We herein review genetic, pathological, and molecular evidence for the emerging link between autophagy dysfunction and lysosomal storage disorders such as Niemann-Pick type C, progressive myoclonic epilepsies such as Lafora disease, and leukodystrophies such as Alexander disease. We also discuss the recent discovery of genetically deranged autophagy in Vici syndrome, a multisystem disorder, and the implications for the role of autophagy in development and disease. Deciphering the exact mechanism by which autophagy contributes to disease pathology may open novel therapeutic avenues to treat neurodegeneration. To this end, an outlook on novel therapeutic approaches targeting autophagy concludes this review. P ediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. Although the age of onset and the clinical course are variable, neurodegenerative disorders of childhood are characterized by progressive neurologic and cognitive dysfunction with loss of speech, vision, hearing, and motor skills, and a frequent association with seizures, feeding difficulties, and failure to thrive. The degenerative process can affect white and gray matter and spreads in a disease-specific manner. Current genetic and biochemical testing and neuroimaging can establish a diagnosis. The outcome for most diseases, however, is still poor, as therapeutic approaches are limited.Accumulation of proteins, polysaccharides, and lipids are common mechanisms shared by major adult-onset neurodegenerative diseases 1-3 and many neurodegenerative diseases of childhood. 4 These conditions are, therefore, often referred to as "storage diseases" or "proteinopathies. " Cells and postmitotic cells such as neurons, in particular, rely on effective cargo targeting, tagging, transportation, and degradation to maintain intracellular homeostasis under normal conditions and metabolic stress. Within this network, autophagy plays an indispensible role by eliminating misfolded and aggregated proteins, lipids, saccharides, and damaged organelles. Recent evidence suggests that autophagy is dysregulated in a number of pediatric neurodegenerative and metabolic diseases. AUTOPHAGY: AN OVERVIEWAutophagy describes intracellular pathways that converge into degradation of target material in lysosomes. 5 The route of cargo delivery to the lysosome distinguishes th...

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Section: Reviewmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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“…C. elegans epg-5 mutant and knockdown of mEPG5 in mammalian cells show accumulation of non-degradative autolysosomes, indicating the role of EPG-5/mEPG5 in autolysosome maturation [32]. It was later shown that knockdown of EPG5 in HeLa cells results in another defect in the endocytic pathway [33].…”

Section: Vici Syndromementioning

confidence: 99%

“…A recent study in C. elegans identified EI24/PIG8, whose human homolog was reported to be mutated in breast cancers [84], as a critical factor of autophagic degradation [32]. However, it remains to be clarified whether EI24-mutated human breast cancer cells indeed show decreased autophagic activity.…”

Section: Cancermentioning

confidence: 99%

Autophagy and human diseases

2013

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Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation. Since the discovery of autophagy-related (Atg) genes in the 1990s, there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models. However, direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently. There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases, infectious diseases, and cancers. Here, we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases. Current autophagy-modulating compounds in clinical trials are also summarized.

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“…VMP1 has been previously shown to form dot-like accumulations on the ER, in addition to the ER network and the Golgi, regardless of nutrient conditions [20]. VMP1 was originally identified in C. elegans using a screen designed to identify eukaryotic autophagy genes [72]. Since VMP1 dots can be seen without autophagy induction and therefore precedes the accumulation of other Atg proteins, VMP1 may be marking autophagosome formation sites.…”

Section: Autophagosome Formation On the Ermentioning

confidence: 99%

A current perspective of autophagosome biogenesis

2013

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Autophagy is a bulk degradation system induced by cellular stresses such as nutrient starvation. Its function relies on the formation of double-membrane vesicles called autophagosomes. Unlike other organelles that appear to stably exist in the cell, autophagosomes are formed on demand, and once their formation is initiated, it proceeds surprisingly rapidly. How and where this dynamic autophagosome formation takes place has been a long-standing question, but the discovery of Atg proteins in the 1990's significantly accelerated our understanding of autophagosome biogenesis. In this review, we will briefly introduce each Atg functional unit in relation to autophagosome biogenesis, and then discuss the origin of the autophagosomal membrane with an introduction to selected recent studies addressing this problem.

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C. elegans Screen Identifies Autophagy Genes Specific to Multicellular Organisms

Cited by 370 publications

References 24 publications

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

Autophagy and human diseases

A current perspective of autophagosome biogenesis

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