A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation

Liu, Qing Yan; Lei, Joy X; Sikorska, Marianna; Liu, Rugao

doi:10.1186/1750-1326-3-4

Cited by 46 publications

(40 citation statements)

References 34 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, alterations in ATP6V0C have yet to be reported in human neurodegenerative disease. A previous study has indicated increased expression of the E3 ubiquitin ligase protein RNF182 in Alzheimer's disease brain [49]. RNF182 was shown using in vitro studies to bind ATP6V0C with high affinity and target it for degradation [49], thus suggesting the potential for disruption of ATP6V0C function in Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study has indicated increased expression of the E3 ubiquitin ligase protein RNF182 in Alzheimer's disease brain [49]. RNF182 was shown using in vitro studies to bind ATP6V0C with high affinity and target it for degradation [49], thus suggesting the potential for disruption of ATP6V0C function in Alzheimer's disease. As such, future investigation of ATP6V0C expression patterns in brains of neurodegenerative disease patients is warranted.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease

et al. 2014

View full text Add to dashboard Cite

ATP6V0C is the bafilomycin A1-binding subunit of vacuolar ATPase, an enzyme complex that critically regulates vesicular acidification. We and others have shown previously that bafilomycin A1 regulates cell viability, autophagic flux and metabolism of proteins that accumulate in neurodegenerative disease. To determine the importance of ATP6V0C for autophagy-lysosome pathway function, SH-SY5Y human neuroblastoma cells differentiated to a neuronal phenotype were nucleofected with non-target or ATP6V0C siRNA and following recovery were treated with either vehicle or bafilomycin A1 (0.3–100 nM) for 48 h. ATP6V0C knockdown was validated by quantitative RT-PCR and by a significant decrease in Lysostracker Red staining. ATP6V0C knockdown significantly increased basal levels of microtubule-associated protein light chain 3-II (LC3-II), α-synuclein high molecular weight species and APP C-terminal fragments, and inhibited autophagic flux. Enhanced LC3 and LAMP-1 co-localization following knockdown suggests that autophagic flux was inhibited in part due to lysosomal degradation and not by a block in vesicular fusion. Knockdown of ATP6V0C also sensitized cells to the accumulation of autophagy substrates and a reduction in neurite length following treatment with 1 nM bafilomycin A1, a concentration that did not produce such alterations in non-target control cells. Reduced neurite length and the percentage of propidium iodide-positive dead cells were also significantly greater following treatment with 3 nM bafilomycin A1. Together these results indicate a role for ATP6V0C in maintaining constitutive and stress-induced ALP function, in particular the metabolism of substrates that accumulate in age-related neurodegenerative disease and may contribute to disease pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease

et al. 2014

View full text Add to dashboard Cite

show abstract

“…HRD1 regulates levels of APP in the AD brains in an Ubdependent manners (Kaneko et al 2010). RNF182 is upregulated in the brain of AD patients where it targets ATP6VOC subunit in E2-dependent manners (Liu et al 2008). In addition to the deposition of toxic proteins, impairment of nerve cells could be another cause of AD.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Ubiquitin proteasome system networks in the neurological disorders

Anuppalle¹,

Maddirevula²,

Huh³

et al. 2013

Animal Cells and Systems

View full text Add to dashboard Cite

Human neurological disorders are associated with brain-enriched proteins in a major way. Homeostasis of such proteins is a critical event in brain functioning and development. Neuropathological studies of most common neurological disorders clearly show that accumulated, misfolded, mutant proteins are the preliminary causes for such disorders. Studies in the past few decades suggest that the ubiquitin proteasome system (UPS) network is a critical regulator of protein levels mammalian cells. To date, various proteins and substrates in UPS associated with neurological disorders have been identified, but molecular mechanisms and how they are associated with pathogenesis of neurological disorders are poorly understood. Understanding UPS network may set a new window to understand the pathogenesis of neurological disorders. Here we are reporting the current studies of UPS components in major neurological disorders, such as Parkinson's, Alzheimer's, autistic spectrum disorders, Huntington's, and multiple sclerosis.

show abstract

“…Modifying these PROTAC molecules to bind a brain-specific E3 ligase, such as TRIM9 128 or RNF182 129 for example, may reduce systemic effect. It should also be noted that targeting cIAP1 targetting by using bestatin in PROTAC design has been highlighted as problematic due to bestatin causing the degradation of cIAP1 which can in turn trigger apoptosis.…”

Section: Proteolysis Targeting Chimera (Protac)mentioning

confidence: 99%

Proteostasis in Huntington’s Disease: Disease Mechanisms and Therapeutic Opportunities

Harding

Tong

2018

Preprint

View full text Add to dashboard Cite

Abstract:Many neurodegenerative diseases are characterised by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons.Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington's disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular the ubiquitin proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review.

show abstract

A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation

Cited by 46 publications

References 34 publications

ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease

ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease

Ubiquitin proteasome system networks in the neurological disorders

Proteostasis in Huntington’s Disease: Disease Mechanisms and Therapeutic Opportunities

Contact Info

Product

Resources

About

A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer's patients and targets ATP6V0C for degradation

Cited by 46 publications

References 34 publications

ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease

ATP6V0C Knockdown in Neuroblastoma Cells Alters Autophagy-Lysosome Pathway Function and Metabolism of Proteins that Accumulate in Neurodegenerative Disease

Ubiquitin proteasome system networks in the neurological disorders

Proteostasis in Huntington&rsquo;s Disease: Disease Mechanisms and Therapeutic Opportunities

Contact Info

Product

Resources

About

Proteostasis in Huntington’s Disease: Disease Mechanisms and Therapeutic Opportunities