Mice deficient in <i>Epg5</i> exhibit selective neuronal vulnerability to degeneration

Zhao, Hongyu; Zhao, Yan; Wang, Xingwei; Xu, Lanjun; Ma, Lin; Feng, Du; Chen, Quan; Kovács, Attila; Fan, Dongsheng; Zhang, Hong

doi:10.1083/jcb.201211014

Cited by 111 publications

(147 citation statements)

References 25 publications

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“…39,40 Supporting this idea, a recently published study in Epg5-deficient mice demonstrated selective neurodegeneration of cortical and spinal cord motor neurons leading to a phenotype that resembles key features of amyotrophic lateral sclerosis. 41 Accumulation of p62 and ubiquitin-positive inclusions were found in neurons and glia cells, underscoring impairment of autophagosome maturation and autophagic flux. 41 Further characterizing findings in Vici syndrome and EPG5-deficient mice might indeed enhance our understanding of the detrimental consequences of deficits in late stages of the autophagic pathway for neuronal maturation, integrity, and neurodegeneration.…”

Section: Autophagy In Pediatric Brain Diseasesmentioning

confidence: 99%

“…41 Accumulation of p62 and ubiquitin-positive inclusions were found in neurons and glia cells, underscoring impairment of autophagosome maturation and autophagic flux. 41 Further characterizing findings in Vici syndrome and EPG5-deficient mice might indeed enhance our understanding of the detrimental consequences of deficits in late stages of the autophagic pathway for neuronal maturation, integrity, and neurodegeneration. Likewise, exploring the mitochondrial abnormalities observed in Vici syndrome could further facilitate our insights into the role of autophagy in maintaining mitochondrial quality and function.…”

Section: Autophagy In Pediatric Brain Diseasesmentioning

confidence: 99%

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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: Autophagy In Pediatric Brain Diseasesmentioning

confidence: 99%

Section: Autophagy In Pediatric Brain Diseasesmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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“…However, as EPG5 is also involved in the endocytic pathway, it is important to examine whether dysregulated endocytic trafficking also contributes to the pathogenesis of Vici syndrome. Furthermore, the Epg5-deficient mice display only some features of Vici syndrome [33,34]. For example, although patients with Vici syndrome demonstrate facial dysmorphism and cataracts, these features are not marked in the Epg5-deficient mice.…”

Section: Vici Syndromementioning

confidence: 99%

“…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]. By using fibroblasts derived from patients with Vici syndrome, Cullup et al showed that autophagic flux is blocked and the autophagy adapters NBR1 and SQSTM1/p62 accumulate, confirming the decreased autophagic activity in Vici syndrome [27].…”

Section: Vici Syndromementioning

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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“…This disorder is caused by recessive mutations in EPG5, an autophagy gene identified first in Caenorhabditis elegans (91). Epg5-null mice develop ALS-like features (92).…”

Section: Mechanisms Of Autophagy Upregulationmentioning

confidence: 99%