Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases

Zheng, Chen; Geetha, Thangiah; Babu,

doi:10.1159/000367694

Cited by 37 publications

(26 citation statements)

References 199 publications

(226 reference statements)

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“…Common compromised processes are mitochondrial function upon oxidative stress, RNA function and metabolism, the UPS system, and the altered solubility of specific disease-associated proteins (14, 105, 126). The UPS system is being extensively investigated in this context, and failure of proper protein degradation plays an important part in the pathogenesis of neurodegenerative diseases (149). SUMOylation is involved in multiple neurodegenerative diseases, where key proteins were found to be SUMO modified.…”

Section: Sumoylation Regulates Protein Aggregation In Neurodegeneratimentioning

confidence: 99%

Ubiquitin-dependent and independent roles of SUMO in proteostasis

Liebelt

Vertegaal

2016

American Journal of Physiology-Cell Physiology

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Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options.

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Section: Sumoylation Regulates Protein Aggregation In Neurodegeneratimentioning

confidence: 99%

Ubiquitin-dependent and independent roles of SUMO in proteostasis

Liebelt

Vertegaal

2016

American Journal of Physiology-Cell Physiology

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“…In addition to misfolded and aggregated α-synuclein, other proteins, such as components of the ubiquitin proteasome system (UPS) and chaperones, have also been detected in Lewy bodies [8,9], indicating the unsuccessful attempt of UPS to remove the proteinaceous aggregates. Many recent reports indicated altered protein quality control and UPS impairment as being among the main causative factors involved in many neurodegenerative disorders, including PD [10,11].…”

Section: Introductionmentioning

confidence: 99%

Effect of Curcumin on Protein Damage Induced by Rotenone in Dopaminergic PC12 Cells

Buratta

Chiaradia

Tognoloni

et al. 2020

IJMS

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Oxidative stress is considered to be a key factor of the pathogenesis of Parkinson’s disease, a multifactorial neurodegenerative disorder characterized by reduced dopaminergic neurons in the substantia nigra pars compacta and accumulated protein aggregates. Rotenone is a worldwide-used pesticide that induces the most common features of Parkinson’s by direct inhibition of the mitochondrial complex I. Rotenone-induced Parkinson’s models, as well as brain tissues from Parkinson’s patients, are characterized by the presence of both lipid peroxidation and protein oxidation markers resulting from the increased level of free radical species. Oxidation introduces several modifications in protein structure, including carbonylation and nitrotyrosine formation, which severely compromise cell function. Due to the link existing between oxidative stress and Parkinson’s disease, antioxidant molecules could represent possible therapeutic tools for this disease. In this study, we evaluated the effect of curcumin, a natural compound known for its antioxidant properties, in dopaminergic PC12 cells treated with rotenone, a cell model of Parkinsonism. Our results demonstrate that the treatment of PC12 cells with rotenone causes severe protein damage, with formation of both carbonylated and nitrotyrosine-derived proteins, whereas curcumin (10 µM) co-exposure exerts protective effects by reducing the levels of oxidized proteins. Curcumin also promotes proteasome activation, abolishing the inhibitory effect exerted by rotenone on this degradative system.

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“…These mechanisms, which are often referred to as the cellular proteostasis network, prevent the accumulation of toxic levels of unfolded or misfolded proteins by breaking the proteins down into polypeptide chains . Any disturbance in this system causes proteins in different parts of the body to accumulate and promotes severe neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion or polyglutamine diseases .…”

Section: Introductionmentioning

confidence: 99%

The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease

Gadhave

Bolshette

Ahire

et al. 2016

J Cellular Molecular Medi

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The cellular quality control system degrades abnormal or misfolded proteins and consists of three different mechanisms: the ubiquitin proteasomal system (UPS), autophagy and molecular chaperones. Any disturbance in this system causes proteins to accumulate, resulting in neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, Huntington's disease and prion or polyglutamine diseases. Alzheimer's disease is currently one of the most common age‐related neurodegenerative diseases. However, its exact cause and pathogenesis are unknown. Currently approved medications for AD provide symptomatic relief; however, they fail to influence disease progression. Moreover, the components of the cellular quality control system represent an important focus for the development of targeted and potent therapies for managing AD. This review aims to evaluate whether existing evidence supports the hypothesis that UPS impairment causes the early pathogenesis of neurodegenerative disorders. The first part presents basic information about the UPS and its molecular components. The next part explains how the UPS is involved in neurodegenerative disorders. Finally, we emphasize how the UPS influences the management of AD. This review may help in the design of future UPS‐related therapies for AD.

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Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases

Cited by 37 publications

References 199 publications

Ubiquitin-dependent and independent roles of SUMO in proteostasis

Ubiquitin-dependent and independent roles of SUMO in proteostasis

Effect of Curcumin on Protein Damage Induced by Rotenone in Dopaminergic PC12 Cells

The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease

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