Misfolded PrP and a novel mechanism of proteasome inhibition

André, Ralph; Tabrizi, Sarah J.

doi:10.4161/pri.6.1.18272

Cited by 38 publications

(45 citation statements)

References 28 publications

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“…Therefore, proteasome cannot digest protein aggregates that cannot be easily unfolded. For example, β-sheet-rich PrP aggregates were shown to block the opening of the 20S proteasome particle, further reducing proteasomal activity (Andre and Tabrizi, 2012). Following ubiquitination and aggregation, tau in AD binds the recognition site of the 19S catalytic particle and block its gate (Dantuma and Lindsten, 2010; Tai et al, 2012).…”

Section: Degradation Of Misfolded Proteins By Molecular Chaperones Thmentioning

confidence: 99%

Protein Quality Control by Molecular Chaperones in Neurodegeneration

2017

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Protein homeostasis (proteostasis) requires the timely degradation of misfolded proteins and their aggregates by protein quality control (PQC), of which molecular chaperones are an essential component. Compared with other cell types, PQC in neurons is particularly challenging because they have a unique cellular structure with long extensions. Making it worse, neurons are postmitotic, i.e., cannot dilute toxic substances by division, and, thus, are highly sensitive to misfolded proteins, especially as they age. Failure in PQC is often associated with neurodegenerative diseases, such as Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), and prion disease. In fact, many neurodegenerative diseases are considered to be protein misfolding disorders. To prevent the accumulation of disease-causing aggregates, neurons utilize a repertoire of chaperones that recognize misfolded proteins through exposed hydrophobic surfaces and assist their refolding. If such an effort fails, chaperones can facilitate the degradation of terminally misfolded proteins through either the ubiquitin (Ub)-proteasome system (UPS) or the autophagy-lysosome system (hereafter autophagy). If soluble, the substrates associated with chaperones, such as Hsp70, are ubiquitinated by Ub ligases and degraded through the proteasome complex. Some misfolded proteins carrying the KFERQ motif are recognized by the chaperone Hsc70 and delivered to the lysosomal lumen through a process called, chaperone-mediated autophagy (CMA). Aggregation-prone misfolded proteins that remain unprocessed are directed to macroautophagy in which cargoes are collected by adaptors, such as p62/SQSTM-1/Sequestosome-1, and delivered to the autophagosome for lysosomal degradation. The aggregates that have survived all these refolding/degradative processes can still be directly dissolved, i.e., disaggregated by chaperones. Studies have shown that molecular chaperones alleviate the pathogenic symptoms by neurodegeneration-causing protein aggregates. Chaperone-inducing drugs and anti-aggregation drugs are actively exploited for beneficial effects on symptoms of disease. Here, we discuss how chaperones protect misfolded proteins from aggregation and mediate the degradation of terminally misfolded proteins in collaboration with cellular degradative machinery. The topics also include therapeutic approaches to improve the expression and turnover of molecular chaperones and to develop anti-aggregation drugs.

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Section: Degradation Of Misfolded Proteins By Molecular Chaperones Thmentioning

confidence: 99%

Protein Quality Control by Molecular Chaperones in Neurodegeneration

2017

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“…Progressive inhibition of proteasome activity results from direct binding of accumulating PrP Sc to the 20S CP, which stabilizes the closed conformation of the gate and prevents substrate entry into the proteasome (99). The onset of proteasome dysfunction is closely correlated with PrP Sc deposition, preceding the earliest behavioral deficits and neuronal loss (100).…”

Section: Correlation Between 26s Proteasome Dysfunction and Neurodegementioning

confidence: 99%

Precise assembly and regulation of 26S proteasome and correlation between proteasome dysfunction and neurodegenerative diseases

Im¹,

Chung²

2016

BMB Reports

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Neurodegenerative diseases (NDs) often involve the formation of abnormal and toxic protein aggregates, which are thought to be the primary factor in ND occurrence and progression. Aged neurons exhibit marked increases in aggregated protein levels, which can lead to increased cell death in specific brain regions. As no specific drugs/therapies for treating the symptoms or/and progression of NDs are available, obtaining a complete understanding of the mechanism underlying the formation of protein aggregates is needed for designing a novel and efficient removal strategy. Intracellular proteolysis generally involves either the lysosomal or ubiquitin-proteasome system. In this review, we focus on the structure and assembly of the proteasome, proteasome-mediated protein degradation, and the multiple dynamic regulatory mechanisms governing proteasome activity. We also discuss the plausibility of the correlation between changes in proteasome activity and the occurrence of NDs. [BMB Reports 2016; 49(9): 459-473]

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“…It is widely accepted that autophagy-lysosome system, rather than the ubiquitin-proteasome system, is the main degrading pathway for neurotoxic protein aggregates. In prion disease, PrP Sc is able to bind directly to 26S proteasome and inhibits substrate entry [31][32][33]. Other components of proteasome (19S and 20S) are blocked by different mechanisms which indicate a functional impairment of proteasome in prion disease [12].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy

et al. 2016

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Polo-like kinase 3 (PLK3) is the main cause of cell cycle reentry-related neuronal apoptosis which has been implicated in the pathogenesis of prion diseases. Previous work also showed the regulatory activity of exogenous PLK3 on the degradation of PrP (prion protein) mutants and pathogenic PrP; however, the precise mechanisms remain unknown. In this study, we identified that the overexpression of PLK3-mediated degradation of PrP mutant and PrP was repressed by lysosome rather than by proteasomal and macroautophagy inhibitors. Core components of chaperone-mediated autophagy (CMA) effectors, lysosome-associated membrane protein type 2A (LAMP2a), and heat shock cognate protein 70 (Hsc70) are markedly decreased in the HEK293T cells expressing PrP mutant and scrapie-infected cell line SMB-S15. Meanwhile, PrP mutant showed ability to interact with LAMP2a and Hsc70. Overexpression of PLK3 sufficiently increased the cellular levels of LAMP2a and Hsc70, accompanying with declining the accumulations of PrP mutant and PrP. The kinase domain (KD) of PLK3 was responsible for elevating LAMP2a and Hsc70. Knockdown of endogenous PLK3 enhanced the activity of macroautophagy in the cultured cells. Moreover, time-dependent reductions of LAMP2a and Hsc70 were also observed in the brain tissues of hamster-adapted scrapie agent 263K-infected hamsters, indicating an impairment of CMA during prion infection. Those data indicate that the overexpression of PLK3-mediated degradation of abnormal PrP is largely dependent on CMA pathway.

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Misfolded PrP and a novel mechanism of proteasome inhibition

Cited by 38 publications

References 28 publications

Protein Quality Control by Molecular Chaperones in Neurodegeneration

Protein Quality Control by Molecular Chaperones in Neurodegeneration

Precise assembly and regulation of 26S proteasome and correlation between proteasome dysfunction and neurodegenerative diseases

Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy

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