Upregulation of immunoproteasome PSMB8 is associated with Parkinson’s disease

Nguyen, Huu Dat; Kim, Young Eun; Nguyen, Linh Thi Nhat; Kwak, In Hee; Lee, Yoon Kyoung; Kim, Yun Joong; Nguyen, Thi Viet Ha; Pham, Hong Ngoc Thuy; Ma, Hyeo-Il

doi:10.1016/j.parkreldis.2023.105797

Cited by 3 publications

(4 citation statements)

References 37 publications

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“…The nodes included 12 of the cDEGs (Table 1). Among these, increased levels and activity of PSMB8, Proteasome Subunit Beta 8, has been previously reported in postmortem human brains with PD 31 . Another gene, GRIA1, a subunit of AMPA receptors, has been observed to be significantly lowered in the SNpc of PD patients compared to normal samples 32 .…”

Section: Resultsmentioning

confidence: 80%

Unveiling the genes and pathways that are dysregulated in dopaminergic neurons during both familial and sporadic Parkinson’s disease

Padhan,

Verma

2024

Preprint

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Identification of shared dysregulated genes and molecular mechanisms responsible for dopaminergic (DA) neuronal death in familial and sporadic forms of Parkinson’s disease (PD) can offer the potential for common therapies in both types of PD. The gene expression profiles of DA neurons with sporadic and familial PD backgrounds and healthy DA neurons were obtained from the Gene Expression Omnibus database. Overlapping differentially expressed genes and hub genes were identified. These genes were subjected to Gene Ontology and Reactome pathway enrichment analyses. The roles of a select few differentially expressed genes inC. elegansDA neuron health were assessed. 40 genes, including 12 hub genes, were found dysregulated in DA neurons with sporadic and familial PD. Altering the expression of some of these genes in wild-typeCaenorhabditis eleganspromoted DA neuron degeneration and function. The study unveils shared molecular mechanisms in DA neurons for familial and sporadic PD, potentially driving DA neuron degeneration. Understanding their roles may lead to targeted therapies, early detection, and intervention.In vivoexperiments support our hypothesis, suggesting the implication of these genes in PD neurodegeneration and neuroprotection.

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Section: Resultsmentioning

confidence: 80%

Unveiling the genes and pathways that are dysregulated in dopaminergic neurons during both familial and sporadic Parkinson’s disease

Padhan,

Verma

2024

Preprint

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“…Induced expression of POMP enhances proteasomal activity and PLK2 degradation, alleviating α-Syn aggregation and neuronal loss in PD . Recently studies emerged directly connecting increased expression of PSMB8 with development of PD . Thus, therapies based on the intensification of i20S assembly seem to be a promising approach in novel PD treatment.…”

Section: Immunoproteasome In Neuroinflammatory-related Disordersmentioning

confidence: 99%

“…69 Recently studies emerged directly connecting increased expression of PSMB8 with development of PD. 70 Thus, therapies based on the intensification of i20S assembly seem to be a promising approach in novel PD treatment.…”

Section: Neuroinflammatory-related Disordersmentioning

confidence: 99%

Targeting Microglial Immunoproteasome: A Novel Approach in Neuroinflammatory-Related Disorders

Malek,

Gladysz,

Stelmach

et al. 2024

ACS Chem. Neurosci.

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It is widely acknowledged that the aging process is linked to the accumulation of damaged and misfolded proteins. This phenomenon is accompanied by a decrease in proteasome (c20S) activity, concomitant with an increase in immunoproteasome (i20S) activity. These changes can be attributed, in part, to the chronic neuroinflammation that occurs in brain tissues. Neuroinflammation is a complex process characterized by the activation of immune cells in the central nervous system (CNS) in response to injury, infection, and other pathological stimuli. In certain cases, this immune response becomes chronic, contributing to the pathogenesis of various neurological disorders, including chronic pain, Alzheimer's disease, Parkinson's disease, brain traumatic injury, and others. Microglia, the resident immune cells in the brain, play a crucial role in the neuroinflammatory response. Recent research has highlighted the involvement of i20S in promoting neuroinflammation, increased activity of which may lead to the presentation of self-antigens, triggering an autoimmune response against the CNS, exacerbating inflammation, and contributing to neurodegeneration. Furthermore, since i20S plays a role in breaking down accumulated proteins during inflammation within the cell body, any disruption in its activity could lead to a prolonged state of inflammation and subsequent cell death. Given the pivotal role of i20S in neuroinflammation, targeting this proteasome subtype has emerged as a potential therapeutic approach for managing neuroinflammatory diseases. This review delves into the mechanisms of neuroinflammation and microglia activation, exploring the potential of i20S inhibitors as a promising therapeutic strategy for managing neuroinflammatory disorders.

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“…Our study presents an analysis of 17 neddylation-related genes, embodying a wide spectrum of biological functions, notably in protein degradation and ubiquitination exemplified by PSMB8, PSMB9, PSMB10, F-box protein 41 (FBXO41), FBXO17, F-box and leucine-rich repeat protein 16 (FBXL16), FBXL8 [49][50][51][52][53][54][55], cell cycle regulation and apoptosis including baculoviral IAP repeat containing 5 (BIRC5), denticleless E3 ubiquitin protein ligase homolog (DTL) [56,57], immune response and inflammation mediated by PSMB8, PSMB9, PSMB10, and ubiquitin D (UBD) [58][59][60][61], as well as DNA repair and genomic stability with a pivotal contribution from DNA damage-binding protein 2 (DDB2) [62].…”

mentioning

confidence: 99%

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing

Liu,

Wu,

Wang

et al. 2024

Pharmaceuticals

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Background: Neddylation, a post-translational modification process, plays a crucial role in various human neoplasms. However, its connection with kidney renal clear cell carcinoma (KIRC) remains under-researched. Methods: We validated the Gene Set Cancer Analysis Lite (GSCALite) platform against The Cancer Genome Atlas (TCGA) database, analyzing 33 cancer types and their link with 17 neddylation-related genes. This included examining copy number variations (CNVs), single nucleotide variations (SNVs), mRNA expression, cellular pathway involvement, and methylation. Using Gene Set Variation Analysis (GSVA), we categorized these genes into three clusters and examined their impact on KIRC patient prognosis, drug responses, immune infiltration, and oncogenic pathways. Afterward, our objective is to identify genes that exhibit overexpression in KIRC and are associated with an adverse prognosis. After pinpointing the specific target gene, we used the specific inhibitor MLN4924 to inhibit the neddylation pathway to conduct RNA sequencing and related in vitro experiments to verify and study the specificity and potential mechanisms related to the target. This approach is geared towards enhancing our understanding of the prognostic importance of neddylation modification in KIRC. Results: We identified significant CNV, SNV, and methylation events in neddylation-related genes across various cancers, with notably higher expression levels observed in KIRC. Cluster analysis revealed a potential trade-off in the interactions among neddylation-related genes, where both high and low levels of gene expression are linked to adverse prognoses. This association is particularly pronounced concerning lymph node involvement, T stage classification, and Fustat score. Simultaneously, our research discovered that PSMB10 exhibits overexpression in KIRC when compared to normal tissues, negatively impacting patient prognosis. Through RNA sequencing and in vitro assays, we confirmed that the inhibition of neddylation modification could play a role in the regulation of various signaling pathways, thereby influencing the prognosis of KIRC. Moreover, our results underscore PSMB10 as a viable target for therapeutic intervention in KIRC, opening up novel pathways for the development of targeted treatment strategies. Conclusion: This study underscores the regulatory function and potential mechanism of neddylation modification on the phenotype of KIRC, identifying PSMB10 as a key regulatory target with a significant role in influencing the prognosis of KIRC.

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Upregulation of immunoproteasome PSMB8 is associated with Parkinson’s disease

Cited by 3 publications

References 37 publications

Unveiling the genes and pathways that are dysregulated in dopaminergic neurons during both familial and sporadic Parkinson’s disease

Unveiling the genes and pathways that are dysregulated in dopaminergic neurons during both familial and sporadic Parkinson’s disease

Targeting Microglial Immunoproteasome: A Novel Approach in Neuroinflammatory-Related Disorders

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing

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