The ubiquitin proteasome system in neurodegenerative diseases: Culprit, accomplice or victim?

Dennissen, Frank J.A.; Kholod, Natalia; Leeuwen, Fred W. van

doi:10.1016/j.pneurobio.2012.01.003

Cited by 113 publications

(88 citation statements)

References 229 publications

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“…The formation of these misfolded by-products is thought to impair proteasome activity and lead to the formation of ubiquitylated bodies, a cardinal feature of many neurodegenerative diseases (99). However, monoubiquitin and diubiquitin appear to control selectively the deubiquinating activities of ubiquitin C-terminal hydrolases-L1 (UCH-L1) and -L3 (UCH-L3), respectively (130).…”

Section: Discussionmentioning

confidence: 99%

“…Protein aggregation caused by protein misfolding is often associated with the formation of ubiquitylated bodies, a hallmark feature of many neurodegenerative diseases (99). Furthermore, prior studies have implicated a role of Ranbp2 in the degradation of properly folded proteins by the 26 S proteasome as reflected by the accumulation of ubiquitylated substrates and reporters of the ubiquitin-proteasome system upon ectopic expression of CLD alone of Ranbp2 in culture cells (88).…”

Section: R2944a-ha ::Ranbp2mentioning

confidence: 99%

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Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Cho

Patil

Senda

et al. 2014

Journal of Biological Chemistry

157

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Background: Cyclophilins harbor ill-defined chaperone and prolyl isomerase activities toward physiological substrates. Results: Nonoverlapping chaperone or prolyl isomerase activity loss of Ran-binding protein 2 (Ranbp2) cyclophilin domain triggers unique impairments of proteostasis in distinct cell types and ubiquitin-proteasome system. Conclusion: Ranbp2 cyclophilin subdomains present discriminating physiological activities toward substrates or regulation of ubiquitin-proteasome system. Significance: Ranbp2-mediated mechanistic links in proteostasis with physiological and therapeutic relevance are uncovered.The immunophilins, cyclophilins, catalyze peptidyl cis-trans prolyl-isomerization (PPIase), a rate-limiting step in protein folding and a conformational switch in protein function. Cyclophilins are also chaperones. Noncatalytic mutations affecting the only cyclophilins with known but distinct physiological substrates, the Drosophila NinaA and its mammalian homolog, cyclophilin-B, impair opsin biogenesis and cause osteogenesis imperfecta, respectively. However, the physiological roles and substrates of most cyclophilins remain unknown. It is also unclear if PPIase and chaperone activities reflect distinct cyclophilin properties. To elucidate the physiological idiosyncrasy stemming from potential cyclophilin functions, we generated mice lacking endogenous Ran-binding protein-2 (Ranbp2) and expressing bacterial artificial chromosomes of Ranbp2 with impaired C-terminal chaperone and with (Tg-Ranbp2 WT-HA ) or without PPIase activities (Tg-Ranbp2 R2944A-HA ). The transgenic lines exhibit unique effects in proteostasis. Either line presents selective deficits in M-opsin biogenesis with its accumulation and aggregation in cone photoreceptors but without proteostatic impairment of two novel Ranbp2 cyclophilin partners, the cytokine-responsive effectors, STAT3/STAT5. Peptidyl cis-trans-prolyl isomerization is a rate-limiting step in protein folding (1-3). The catalysis of the cis-trans interconversion of the peptidyl-prolyl isomers is catalyzed by peptidylprolyl cis-trans isomerases (PPIase) 5 (4 -6). PPIases compose three families of structurally unrelated proteins, the cyclophilins (CyP), FK506-binding proteins (FKBP), and parvulins (7). * This work was supported, in whole or in part, by National Institutes of Health Grants EY019492, GM083165, and GM083165-03S1 (to P. A. F.), 2P30-EY005722 (to Duke University Eye Center), and 5P30NS061789 (to Duke Neurotransgenic Laboratory). This work was also supported by the Foundation Fighting CyPs and FKBPs are designated also as immunophilins, because they mediate immunosuppression (8,9). This effect is achieved by a gain-of-function mechanism upon binding of the immunosuppressive metabolites, cyclosporin A (CsA) or FK506, to the PPIase active site and formation of a ternary complex with the serine/threonine phosphatase, calcineurin, whose sequestration and inhibition prevents the dephosphorylation and activation of the nuclear factor for activation of T-cells (9 -12). Howe...

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Section: Discussionmentioning

confidence: 99%

Section: R2944a-ha ::Ranbp2mentioning

confidence: 99%

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Cho

Patil

Senda

et al. 2014

Journal of Biological Chemistry

157

View full text Add to dashboard Cite

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“…Since the internalization of plasma membrane proteins through the endocytic pathway can be mediated by non-canonical polyubiquitin chains , the decreased degradation in the presence of proteasome inhibitors can still be attributed to the lysosomes since under these conditions there is a decrease in free ubiquitin levels thus interfering with the ubiquitin-mediated internalization process . Dysfunction of the ubiquitination and deubiquitination machineries, mutations in ubiquitin, proteasomal impairment, and mutations in proteasome substrates affecting their rate of degradation underlie the pathogenesis of many neurodegenerative diseases (Dennissen et al, 2012). For instance, the ataxic mouse (ax J ), which results from a mutation in the ataxia gene encoding for the DUB Usp14, shows deficits in presynaptic neurotransmitter release and short-term plasticity (Wilson et al, 2002), in addition to a 35% decrease in free ubiquitin levels when compared to wildtype mice .…”

Section: Role Of Ups In Nervous Systemmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

117

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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“…As UPS is the most important pathway for selective degradation of proteins, it is likely involved in progression of neurodegeneration. 44 Similarly, it has been also indicated that many of the cell deathinducing or -inhibiting proteins are targets for UPS-mediated degradation. 45 Therefore, prolonged failure and impairment in UPS have been implicated, either as a primary cause or secondary consequences in the pathogenesis of numerous neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

et al. 2015

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Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase and its dysregulation is implicated in neurodegenerative diseases. Likewise, C-terminus of Hsc70-interacting protein (CHIP) is linked to neurological disorders, serving as an E3 ubiquitin ligase for targeting damaged or toxic proteins for proteasomal degradation. Here, we demonstrate that CHIP is a novel substrate for Cdk5. Cdk5 phosphorylates CHIP at Ser20 via direct binding to a highly charged domain of CHIP. Co-immunoprecipitation and ubiquitination assays reveal that Cdk5-mediated phosphorylation disrupts the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP's E3 ligase activity, resulting in the inhibition of CHIPmediated degradation of tAIF. Lentiviral transduction assay shows that knockdown of Cdk5 or overexpression of CHIP S20A , but not CHIP WT , attenuates tAIF-mediated neuronal cell death induced by hydrogen peroxide. Thus, we conclude that Cdk5-mediated phosphorylation of CHIP negatively regulates its neuroprotective function, thereby contributing to neuronal cell death progression following neurotoxic stimuli.

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The ubiquitin proteasome system in neurodegenerative diseases: Culprit, accomplice or victim?

Cited by 113 publications

References 229 publications

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

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