Inhibition of the Proteasome Regulator PA28 Aggravates Oxidized Protein Overload in the Diabetic Rat Brain

Wu, Dong-gui; Wang, Yu-na; Zhou, Ye; Gao, Han; Zhao, Baosheng

doi:10.1007/s10571-023-01322-y

Cited by 4 publications

(5 citation statements)

References 64 publications

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“…Related studies have shown that proteasome function and PA28α expression are inhibited in the brain of diabetic rats [88] . The PA28 expression in the diabetic brain has a certain regulatory effect on protein metabolism caused by oxidative damage [88] . As suggested above, PSME1 may be a new potential therapeutic target for AD and deserves further investigation.…”

Section: Discussionmentioning

confidence: 93%

“…PA28α is an activator of proteasome, which mainly increases the protein degradation activity of 20S proteasome and participates in MHC-I (major histocompatibility complex I) restricted antigen presentation [86] . Studies have shown that PA28α overexpression in the brain of female mice can effectively prevent protein aggregation in the hippocampus, thereby reducing depression-like behavior and enhancing learning and memory ability [87] . Related studies have shown that proteasome function and PA28α expression are inhibited in the brain of diabetic rats [87] .…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that PA28α overexpression in the brain of female mice can effectively prevent protein aggregation in the hippocampus, thereby reducing depression-like behavior and enhancing learning and memory ability [87] . Related studies have shown that proteasome function and PA28α expression are inhibited in the brain of diabetic rats [87] . The PA28 expression in the diabetic brain has a certain regulatory effect on protein metabolism caused by oxidative damage [87] .…”

Section: Discussionmentioning

confidence: 99%

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Systematic evaluation of multifactorial causal associations for Alzheimer's disease and an interactive platform based on Mendelian randomization analysis——MRAD

Zhao,

Li,

Zhang

et al. 2024

Preprint

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Alzheimer's disease (AD) is a complex degenerative disease of the central nervous system. Traditional epidemiological studies have reported several risk factors for AD. However, most epidemiological studies are insufficient to draw definitive conclusions on causal association due to the potential for reverse causality and confounding bias. Therefore, elucidating its pathogenesis remains challenging. Mendelian randomization (MR) was developed for assessing causality using genetic variants as a new approach in epidemiological research. In this study, we used MR analysis to investigate potential AD risk factors to support extensive AD research. We used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease (n=17,168), Medical laboratory science (n=15,416), Imaging (n=4,896), Anthropometric (n=4,478), Treatment (n=4,546), Molecular trait (n=17,757), Gut microbiota (n=48), Past history (n=668), Family history (n=1,114), and Lifestyle trait (n=7,038). For the convenience of display and operation, an online platform called MRAD has been developed using the Shiny package with MR analysis results. MRAD can be freely accessed online at https://gwasmrad.com/mrad/. Moreover, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. This is one of the first and largest studies in this field. The findings of our research advance understanding of the etiology of AD.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Systematic evaluation of multifactorial causal associations for Alzheimer's disease and an interactive platform based on Mendelian randomization analysis——MRAD

Zhao,

Li,

Zhang

et al. 2024

Preprint

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“…Increased oxidized protein in diabetes is one of the major reasons for diabetic encephalopathy and UPS is known to eliminate the oxidized protein by regulating its proteasomal activity in diabetic rat brain. The silencing of the PA28 subunits, a γ‐interferon‐induced subunit that enhances 20 S proteasome activity, showed increased accumulation of oxidized proteins suggesting the involvement of UPS in the clearance of oxidized proteins in the brain (Wu et al, 2023). Vascular endothelial dysfunction is a life‐threatening condition in diabetic patients.…”

Section: Ups In the Manifestation Of Diabetesmentioning

confidence: 99%

Degradation meets development: Implications in β‐cell development and diabetes

Ashok,

Kalthur,

Kumar

2024

Cell Biology International

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Pancreatic development is orchestrated by timely synthesis and degradation of stage‐specific transcription factors (TFs). The transition from one stage to another stage is dependent on the precise expression of the developmentally relevant TFs. Persistent expression of particular TF would impede the exit from the progenitor stage to the matured cell type. Intracellular protein degradation‐mediated protein turnover contributes to a major extent to the turnover of these TFs and thereby dictates the development of different tissues. Since even subtle changes in the crucial cellular pathways would dramatically impact pancreatic β‐cell performance, it is generally acknowledged that the biological activity of these pathways is tightly regulated by protein synthesis and degradation process. Intracellular protein degradation is executed majorly by the ubiquitin proteasome system (UPS) and Lysosomal degradation pathway. As more than 90% of the TFs are targeted to proteasomal degradation, this review aims to examine the crucial role of UPS in normal pancreatic β‐cell development and how dysfunction of these pathways manifests in metabolic syndromes such as diabetes. Such understanding would facilitate designing a faithful approach to obtain a therapeutic quality of β‐cells from stem cells.

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“…Recently, the role of PA28αβ has been spotlighted, especially within the context of oxidative stress. This regulator has been explored as a component of the pathway of degradation for protein substrates damaged by oxidative stress [ 78 , 79 , 80 ]. Notably, during oxidative challenges PA28αβ, in conjunction with the i20S CP, demonstrates a strong induction: up to three-fold during oxidative stress.…”

Section: Pa28αβmentioning

confidence: 99%

Structure, Function, and Allosteric Regulation of the 20S Proteasome by the 11S/PA28 Family of Proteasome Activators

Thomas,

Salcedo-Tacuma,

Smith

2023

Biomolecules

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The proteasome, a complex multi-catalytic protease machinery, orchestrates the protein degradation essential for maintaining cellular homeostasis, and its dysregulation also underlies many different types of diseases. Its function is regulated by many different mechanisms that encompass various factors such as proteasome activators (PAs), adaptor proteins, and post-translational modifications. This review highlights the unique characteristics of proteasomal regulation through the lens of a distinct family of regulators, the 11S, REGs, or PA26/PA28. This ATP-independent family, spanning from amoebas to mammals, exhibits a common architectural structure; yet, their cellular biology and criteria for protein degradation remain mostly elusive. We delve into their evolution and cellular biology, and contrast their structure and function comprehensively, emphasizing the unanswered questions regarding their regulatory mechanisms and broader roles in proteostasis. A deeper understanding of these processes will illuminate the roles of this regulatory family in biology and disease, thus contributing to the advancement of therapeutic strategies.

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Inhibition of the Proteasome Regulator PA28 Aggravates Oxidized Protein Overload in the Diabetic Rat Brain

Cited by 4 publications

References 64 publications

Systematic evaluation of multifactorial causal associations for Alzheimer's disease and an interactive platform based on Mendelian randomization analysis——MRAD

Systematic evaluation of multifactorial causal associations for Alzheimer's disease and an interactive platform based on Mendelian randomization analysis——MRAD

Degradation meets development: Implications in β‐cell development and diabetes

Structure, Function, and Allosteric Regulation of the 20S Proteasome by the 11S/PA28 Family of Proteasome Activators

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