The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

Nath, Samir R.; Lieberman, Andrew P.

doi:10.3389/fnmol.2017.00078

Cited by 30 publications

(33 citation statements)

References 99 publications

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“…We speculate that these changes result in enhanced proteotoxicity, leading to muscle atrophy through distinct and currently poorly characterized mechanisms. The extent to which proteasome dysfunction occurs in the polyQ diseases has been controversial, as previous findings in vivo have lacked consistency and reproducibility (60). In SBMA, proteasome activity was previously studied in transgenic mice overexpressing AR97Q.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction

Nath

Zhang²,

Gipson

et al. 2018

Journal of Clinical Investigation

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Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age, hormone, and glutamine length dependent and arose due to a toxic gain of function conferred by the mutation. Moreover, altered gene expression was associated with decreased levels of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder.

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Section: Discussionmentioning

confidence: 99%

Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction

Nath

Zhang²,

Gipson

et al. 2018

Journal of Clinical Investigation

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“…These pathways are responsible for the clearance and degradation of misfolded and/or superfluous proteins. It stands to reason that these systems are somewhat compromised in SCA patients, and numerous studies have now shown that these systems do in fact exhibit impairment in SCA diseases [61][62][63][64][65]. The dysregulation is believed to play a role in protein aggregation, as the misfolded polyQ proteins are unable to be effectively degraded, which leads to an increased proportion of aggregates.…”

Section: Protein Aggregation: a Hallmark Featurementioning

confidence: 99%

“…The dysregulation is believed to play a role in protein aggregation, as the misfolded polyQ proteins are unable to be effectively degraded, which leads to an increased proportion of aggregates. These pathways are currently an obvious and attractive therapeutic avenue for SCA diseases [65,66].…”

Section: Protein Aggregation: a Hallmark Featurementioning

confidence: 99%

“…Two important impaired functions of mutant ataxin-3 have been recognised, impaired protein degradation and transcriptional deregulation [65,151]. As ataxin-3 is thought to play a role in transcriptional regulation due to its interaction with transcriptional regulators, deregulation of this process is thought to be a factor when considering SCA3 pathogenesis.…”

Section: Wild-type and Mutant Proteinmentioning

confidence: 99%

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Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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“…Among all the UPS components, E3 ub ligases have gained huge attention in polyQ disease pathogenesis studies (Nath and Lieberman ; Atkin and Paulson ). The E3 ub ligases are responsible for recognizing and recruiting target proteins for ubiquitination, and thus, they confer substrate specificity to UPS (Upadhyay et al .…”

mentioning

confidence: 99%

FipoQ/FBXO33, a Cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein

Chen

Wong

Cheng

et al. 2019

Journal of Neurochemistry

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Polyglutamine (polyQ) diseases describe a group of progressive neurodegenerative disorders caused by the CAG triplet repeat expansion in the coding region of the disease genes. To date, nine such diseases, including spinocerebellar ataxia type 3 (SCA3), have been reported. The formation of SDS‐insoluble protein aggregates in neurons causes cellular dysfunctions, such as impairment of the ubiquitin‐proteasome system, and contributes to polyQ pathologies. Recently, the E3 ubiquitin ligases, which govern substrate specificity of the ubiquitin‐proteasome system, have been implicated in polyQ pathogenesis. The Cullin (Cul) proteins are major components of Cullin‐RING ubiquitin ligases (CRLs) complexes that are evolutionarily conserved in the Drosophila genome. In this study, we examined the effect of individual Culs on SCA3 pathogenesis and found that the knockdown of Cul1 expression enhances SCA3‐induced neurodegeneration and reduces the solubility of expanded SCA3‐polyQ proteins. The F‐box proteins are substrate receptors of Cul1‐based CRL. We further performed a genetic modifier screen of the 19 Drosophila F‐box genes and identified F‐box involved in polyQ pathogenesis (FipoQ) as a genetic modifier of SCA3 degeneration that modulates the ubiquitination and solubility of expanded SCA3‐polyQ proteins. In the human SK‐N‐MC cell model, we identified that F‐box only protein 33 (FBXO33) exerts similar functions as FipoQ in modulating the ubiquitination and solubility of expanded SCA3‐polyQ proteins. Taken together, our study demonstrates that Cul1‐based CRL and its associated F‐box protein, FipoQ/FBXO33, modify SCA3 protein toxicity. These findings will lead to a better understanding of the disease mechanism of SCA3 and provide insights for developing treatments against SCA3. Cover Image for this issue: doi: .

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The Ubiquitination, Disaggregation and Proteasomal Degradation Machineries in Polyglutamine Disease

Cited by 30 publications

References 99 publications

Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction

Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

FipoQ/FBXO33, a Cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein

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