Expanding the role of proteasome homeostasis in Parkinson’s disease: beyond protein breakdown

Bi, Minghong; Du, Xixun; Jiao, Qian; Chen, Xi; Jiang, Hong

doi:10.1038/s41419-021-03441-0

Cited by 47 publications

(31 citation statements)

References 150 publications

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“…Interestingly, the role of ATP/Mg 2+ balance in the context of proteostasis maintenance might be supported by studies reporting decreased levels of Mg 2+ in the brain and cerebrospinal fluid associated with neurodegenerative diseases, including Alzheimer's and Parkinson diseases, as well as with aging [26,27]. Imbalances in the functional state of the UPS and decreased proteasome activity are frequently observed in these conditions [28,29].…”

Section: Resultsmentioning

confidence: 99%

The ATP/Mg2+ Balance Affects the Degradation of Short Fluorogenic Substrates by the 20S Proteasome

Morozov

Astakhova

Erokhov

et al. 2022

MPs

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Proteasomes hydrolyze most cellular proteins. The standard reaction to determine proteasome activity in cellular lysate or elsewhere contains AMC-conjugated peptide substrate, ATP, Mg2+, and DTT. ATP and Mg2+ are included to maintain 26S proteasome functionality. However, most cellular proteasomes are 20S proteasomes, and the effects of ATP on the turnover of fluorogenic substrates by 20S complexes are largely unknown. Here, we evaluated the effect of ATP alone or in combination with Mg2+ on the degradation of AMC-conjugated fluorogenic substrates by purified 20S proteasomes. Degradation of substrates used to determine chymotrypsin-, caspase- and trypsin-like proteasome activities was gradually decreased with the rise of ATP concentration from 0.25 to 10 mM. These effects were not associated with the blockage of the proteasome catalytic subunit active sites or unspecific alterations of AMC fluorescence by the ATP. However, ATP-induced peptide degradation slowdown was rescued by the addition of Mg2+. Moreover, the substrate degradation efficacy was proportional to the Mg2+/ATP ratio, being equal to control values when equimolar concentrations of the molecules were used. The obtained results indicate that when proteasome activity is assessed, the reciprocal effects of ATP and Mg2+ on the hydrolysis of AMC-conjugated fluorogenic substrates by the 20S proteasomes should be considered.

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Section: Resultsmentioning

confidence: 99%

The ATP/Mg2+ Balance Affects the Degradation of Short Fluorogenic Substrates by the 20S Proteasome

Morozov

Astakhova

Erokhov

et al. 2022

MPs

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“…The resulting aberrant protein accumulation probably overloads the cellular ability to degrade rendering the dopaminergic neurons susceptible to external and internal stimuli [ 30 ]. Recently, we have demonstrated the emerging ideas on the regulation of proteasome homeostasis and the strategies for intensifying proteasomal degradation as a promising approach for PD treatment [ 10 ]. Since McNaught and colleagues first reported the impairment of proteasome activities in PD, subsequent studies have verified 26S proteasome dysfunction and its effects on the imbalanced proteostasis [ 12 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…There mainly exists 26S proteasome and immunoproteasome in the central nervous system. Upon certain stimulus, three catalytic subunits β1, β2, and β5 can be replaced by their homologues β1i, β2i, and β5i to form immunoproteasome [ 10 ]. Up to now, the defects in the structure, function and regulation of 26S proteasome in PD patients have been widely reported [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Deficient immunoproteasome assembly drives gain of α-synuclein pathology in Parkinson's disease

Xiao

et al. 2021

Redox Biology

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Aberrant α-synuclein (α-Syn) accumulation resulting from proteasome dysfunction is considered as a prominent factor to initiate and aggravate the neurodegeneration in Parkinson's disease (PD). Although the involvement of 26S proteasome in proteostasis imbalance has been widely accepted, our knowledge about the regulation of immunoproteasome function and its potential role in α-Syn pathology remains limited. Immunoproteasome abundance and proteolytic activities depend on the finely tuned assembly process, especially β-ring formation mediated by the only well-known chaperone proteasome maturation protein (POMP). Here, we identified that α-Syn overexpression was associated with a reduction in immunoproteasome function, which in turn limited the degradation of polo-like kinase 2 (PLK2), exacerbated α-Syn Ser129 phosphorylation and aggregation, ultimately leading to the neurodegeneration. These effects could be dramatically attenuated by β5i overexpression. Mechanistically, α-Syn suppressed the transcriptional regulation of POMP by nuclear factor erythroid 2-related factor 2 (NRF2), thereby preventing the assembly of immunoproteasome β subunits. Dopaminergic neurons-specific overexpression of NRF2-POMP axis effectively rescued the aggregation of α-Syn and PD-like phenotypes. These findings characterized abnormal immunoproteasome assembly as a key contributor governing α-Syn accumulation and neurodegeneration, which might open up a new perspective for the implication of immunoproteasome in PD and provide approaches of manipulating immunoproteasome assembly for therapeutic purposes.

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“…The knockout of Znf179 suppresses the proteasomal increase of TDP-43, which leads to insoluble TDP-43 accumulation and the cytosolic inclusion of TDP-43 [ 51 ]. Ubiquitin ligase CUL2 can modify the misfolded polyubiquitin TDP-43, which is coordinated with the von Hippel Lindau protein [ 52 ].…”

Section: Therapeutic Targets In Upsmentioning

confidence: 99%

Modulating the Ubiquitin–Proteasome System: A Therapeutic Strategy for Autoimmune Diseases

Yadav

Lee

Puranik

et al. 2022

Cells

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Multiple sclerosis (MS) is an autoimmune, neurodegenerative disease associated with the central nervous system (CNS). Autoimmunity is caused by an abnormal immune response to self-antigens, which results in chronic inflammation and tissue death. Ubiquitination is a post-translational modification in which ubiquitin molecules are attached to proteins by ubiquitinating enzymes, and then the modified proteins are degraded by the proteasome system. In addition to regulating proteasomal degradation of proteins, ubiquitination also regulates other cellular functions that are independent of proteasomal degradation. It plays a vital role in intracellular protein turnover and immune signaling and responses. The ubiquitin–proteasome system (UPS) is primarily responsible for the nonlysosomal proteolysis of intracellular proteins. The 26S proteasome is a multicatalytic adenosine-triphosphate-dependent protease that recognizes ubiquitin covalently attached to particular proteins and targets them for degradation. Damaged, oxidized, or misfolded proteins, as well as regulatory proteins that govern many essential cellular functions, are removed by this degradation pathway. When this system is affected, cellular homeostasis is altered, resulting in the induction of a range of diseases. This review discusses the biochemistry and molecular biology of the UPS, including its role in the development of MS and proteinopathies. Potential therapies and targets involving the UPS are also addressed.

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Expanding the role of proteasome homeostasis in Parkinson’s disease: beyond protein breakdown

Cited by 47 publications

References 150 publications

The ATP/Mg2+ Balance Affects the Degradation of Short Fluorogenic Substrates by the 20S Proteasome

The ATP/Mg2+ Balance Affects the Degradation of Short Fluorogenic Substrates by the 20S Proteasome

Deficient immunoproteasome assembly drives gain of α-synuclein pathology in Parkinson's disease

Modulating the Ubiquitin–Proteasome System: A Therapeutic Strategy for Autoimmune Diseases

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