Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Zheng, Qiuyang; Huang, Timothy; Zhang, Lishan; Zhou, Ying; Luo, Hong; Xu, Huaxi; Wang, Xin

doi:10.3389/fnagi.2016.00303

Cited by 246 publications

(188 citation statements)

References 132 publications

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“…1999), a Wnt-pathway gene involved in regulating gene transcription, where increased levels of phosphorylated β-catenin lead to proteasome dysfunction (Ghanevati & Miller 2005). While ubiquitin mediated protein degradation appears to play a significant role in the progression of neurodegeneration and in several pathways critical to healthy cellular function, the exact mechanism is not well understood (Zheng et al 2016). …”

Section: Discussionmentioning

confidence: 99%

Single-Base Resolution Mapping of 5-Hydroxymethylcytosine Modifications in Hippocampus of Alzheimer’s Disease Subjects

2017

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Epigenetic modifications to cytosine have been shown to regulate transcription in cancer, embryonic development, and recently neurodegeneration. While cytosine methylation studies are now common in neurodegenerative research, hydroxymethylation studies are rare, particularly genome-wide mapping studies. As an initial study to analyze 5-hydroxymethylcytosine (5-hmC) in the Alzheimer’s disease (AD) genome, reduced representation hydroxymethylation profiling (RRHP) was used to analyze more than 2 million sites of possible modification in hippocampal DNA of sporadic AD and normal control subjects. Genes with differentially hydroxymethylated regions were filtered based on previously published microarray data for altered gene expression in hippocampal DNA of AD subjects. Our data show significant pathways for altered levels of 5- hmC in the hippocampus of AD subjects compared to age-matched normal controls involved in signaling, energy metabolism, cell function, gene expression, protein degradation, and cell structure and stabilization. Overall, our data suggest a possible role for the dysregulation of epigenetic modifications to cytosine in late stage AD.

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Section: Discussionmentioning

confidence: 99%

Single-Base Resolution Mapping of 5-Hydroxymethylcytosine Modifications in Hippocampus of Alzheimer’s Disease Subjects

2017

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“…[51][52][53] Moreover, UBE2L3 modulates pro-IL-1β processing and mature IL-1β secretion, 54 the deregulation of which pronouncedly intensifies neuronal damage in both AD and IS. 55,56 In addition, UBE2L3 directly interacts with the parkin protein, a ubiquitin-protein ligase that is protective against not only neurodegenerative diseases, [57][58][59] but also cerebral ischemia-reperfusion injury. 60 Nonetheless, there is no conclusive evidence to date demonstrating a causative link between UBE2L3 and AD or IS.…”

Section: Ube2l3 Ydjc and Slc2a11 Genes At 22q11mentioning

confidence: 99%

Shared genes between Alzheimer’s disease and ischemic stroke

Wei

Cui

et al. 2019

CNS Neurosci Ther

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Summary Aims Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP‐based genome‐wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies. Methods Taking advantage of large‐scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene‐based analysis implemented in VEGAS2 and Fisher's meta‐analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD‐ or IS‐associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified. Results 16 AD‐IS pleiotropic genes surpassed the cutoff for Bonferroni‐corrected significance. Notably, MS4A4A and TREM2 , two established AD‐susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature‐based knowledge, most are immune‐relevant genes ( EPHA1 , MS4A4A , UBE2L3 and TREM2 ), implicating crucial roles of the immune system in the pathogenesis of AD and IS. Conclusions The observation that AD and IS had shared disease‐associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.

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“…In our research on melatonin in 3xTg‐AD and NoTg mice, we focused either on putative new pathways or on only marginally addressed ones, to open new pathways in the melatonin mechanisms of action. Such pathways include (a) proteostasis regulation through the ubiquitin‐proteasome system as one of the major cell system for clearance of abnormal proteins; (b) SIRT1 activation as a pathway of cell longevity and neuroprotection, previously suggested as being activated by melatonin; and (c) modulation of growth arrest‐specific gene 6 (Gas6), which is emerging as a novel pharmacological target in neuroinflammation and AD …”

Section: Introductionmentioning

confidence: 99%

Melatonin induces mechanisms of brain resilience against neurodegeneration

Corpas

Griñán-Ferré

Palomera-Ávalos

et al. 2018

Journal of Pineal Research

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Melatonin is an endogenous pleiotropic molecule which orchestrates regulatory functions and protective capacity against age-related ailments. The increase in circulating levels of melatonin through dietary supplements intensifies its health benefits. Investigations in animal models have shown that melatonin protects against Alzheimer's disease (AD)-like pathology, although clinical studies have not been conclusive. We hypothesized that melatonin induces changes in the brain that prevent or attenuate AD by increasing resilience. Therefore, we treated healthy nontransgenic (NoTg) and AD transgenic (3xTg-AD) 6-month-old mice with a daily dose of 10 mg/kg of melatonin until 12 months of age. As expected, melatonin reversed cognitive impairment and dementia-associated behaviors of anxiety and apathy and reduced amyloid and tau burden in 3xTg-AD mice. Remarkably, melatonin induced cognitive enhancement and higher wellness level-related behavior in NoTg mice. At the mechanism level, NF-κB and proinflammatory cytokine expressions were decreased in both NoTg and 3xTg-AD mice. The SIRT1 pathway of longevity and neuroprotection was also activated in both mouse strains after melatonin dosing. Furthermore, we explored new mechanisms and pathways not previously associated with melatonin treatment such as the ubiquitin-proteasome proteolytic system and the recently proposed neuroprotective Gas6/TAM pathway. The upregulation of proteasome activity and the modulation of Gas6 and its receptors by melatonin were similarly displayed by both NoTg and 3xTg-AD mice. Therefore, these results confirm the potential of melatonin treatment against AD pathology, by way of opening new pathways in its mechanisms of action, and demonstrating that melatonin induces cognitive enhancement and brain resilience against neurodegenerative processes.

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Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

Cited by 246 publications

References 132 publications

Single-Base Resolution Mapping of 5-Hydroxymethylcytosine Modifications in Hippocampus of Alzheimer’s Disease Subjects

Single-Base Resolution Mapping of 5-Hydroxymethylcytosine Modifications in Hippocampus of Alzheimer’s Disease Subjects

Shared genes between Alzheimer’s disease and ischemic stroke

Melatonin induces mechanisms of brain resilience against neurodegeneration

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