Selective loss of 20S proteasome α-subunits in the substantia nigra pars compacta in Parkinson's disease

McNaught, Kevin St. P.; Belizaire, Roger; Jenner, Peter; Olanow, C. Warren; Isacson, Ole

doi:10.1016/s0304-3940(02)00296-3

Cited by 220 publications

(150 citation statements)

References 19 publications

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“…Furthermore, with respect to age-matched controls, we observed no significant changes in proteasomal subunit expression levels (either ␣ or ␤, using tubulin or protein disulfide isomerase as controls of protein loading). These preliminary results, obtained with the only human samples made available to us until now, are in sharp contrast with the reported decrease in proteasomal peptidase activities and the unexplained reduction of expression of ␣-subunits (but not ␤-subunits) of the proteasome in the substantia nigra of patients with sporadic PD (23,24). Our preliminary data are in better agreement with those reported by other authors that found no changes in proteasome peptidase activities in brain regions affected with dementia with Lewy body pathology (26).…”

Section: Discussioncontrasting

confidence: 80%

“…22). The possible relevance of proteasome activity in PD pathology is highlighted by reports that describe a decrease in the proteasome peptidase activity in the substantia nigra of sporadic PD patients (23,24), accompanied with a decreased expression of proteasomal ␣-subunits (but not ␤-type subunits) of the proteasome in the same brain region (25). Nevertheless, other authors have found no change of proteasome peptidase activity in human brain regions with dementia with Lewy bodies pathology (26).…”

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confidence: 99%

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α-Synuclein Expression Levels Do Not Significantly Affect Proteasome Function and Expression in Mice and Stably Transfected PC12 Cell Lines

Martin-Clemente

Álvarez-Castelao

Mayo

et al. 2004

Journal of Biological Chemistry

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␣-Synuclein (␣-syn) is a small protein of unknown function that is found aggregated in Lewy bodies, the histopathological hallmark of sporadic Parkinson disease and other synucleinopathies. Mutations in the ␣-syn gene and a triplication of its gene locus have been identified in early onset familial Parkinson disease. ␣-Syn turnover can be mediated by the proteasome pathway. A survey of published data may lead to the suggestion that overexpression of ␣-syn wild type, and/or their variants (A53T and A30P), may produce a decrease in proteasome activity and function, contributing to ␣-syn aggregation. To investigate the relationship between synuclein expression and proteasome function we have studied proteasome peptidase activities and proteasome subunit expression (␣, ␤-constitutive, and inducible) in mice either lacking ␣-syn (knockout mice) or transgenic for human ␣-syn A30P (under control of PrP promoter, at a time when no clear gliosis can be observed). Similar studies are presented in PC12 cells overexpressing enhanced yellow fluorescent protein fusion constructs of human wild type, A30P, and A53T ␣-syn. In these cell lines we have also analyzed the assembly of 20 S proteasome complex and the degradation rate of a well known substrate of the proteasome pathway, I b␣. Overall the data obtained led us to the conclusion that ␣-synuclein expression levels by themselves have no significant effect on proteasome peptidase activity, subunit expression, and proteasome complex assembly and function. These results strengthen the suggestion that other mechanisms resulting in synuclein aggregation (not simply expression levels) may be the key to understand the possible effect of aggregated synuclein on proteasome function.

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Section: Discussioncontrasting

confidence: 80%

mentioning

confidence: 99%

α-Synuclein Expression Levels Do Not Significantly Affect Proteasome Function and Expression in Mice and Stably Transfected PC12 Cell Lines

Martin-Clemente

Álvarez-Castelao

Mayo

et al. 2004

Journal of Biological Chemistry

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“…Furthermore, there are a number of proteasome subunits that are down-regulated in PD nigra. This is consistent with studies that have shown levels of the PA700 proteasome activator are reduced in the SN in PD [16,47].…”

Section: Regulation Of Mitochondrial and Ubiquitin-proteasome Gene Exsupporting

confidence: 93%

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

et al. 2006

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There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin-proteasome system, play an important role in the pathogenesis of Parkinson's disease. We now show that the corresponding pathways of these two systems are linked at the transcriptomic level in Parkinsonian substantia nigra. We examined gene expression in medial and lateral substantia nigra (SN) as well as in frontal cortex using whole genome DNA oligonucleotide microarrays. In this study, we use a hypothesis-driven approach in analysing microarray data to describe the expression of mitochondrial and ubiquitin-proteasomal system (UPS) genes in Parkinson's disease (PD). Although a number of genes showed up-regulation, we found an overall decrease in expression affecting the majority of mitochondrial and UPS sequences. The down-regulated genes include genes that encode subunits of complex I and the Parkinson's-disease-linked UCHL1. The observed changes in expression were very similar for both medial and lateral SN and also affected the PD cerebral cortex. As revealed by "gene shaving" clustering analysis, there was a very significant correlation between the transcriptomic profiles of both systems including in control brains. Therefore, the mitochondria and the proteasome form a higher-order gene regulatory network that is severely perturbed in Parkinson's disease. Our quantitative results also suggest that Parkinson's disease is a disease of more than one cell class, i.e. that it goes beyond the catecholaminergic neuron and involves glia as well.

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“…Given the key role of HSF in the expression of Hsps, including Hsp70 (30), the association of HSF-1 knockdown on Gln-promoted Hsp70 expression was investigated. Transfection with the HSF-1-specific siRNA, siRNA-HSF-1, significantly downregulated levels of HSF-1 mRNA (P<0.01 for 20 and 40 nM) in PC12 cells (Fig.…”

Section: Gln Upregulates Hsp70 Expression In Pc12 Neuroblastoma Cellsmentioning

confidence: 99%

Glutamine promotes Hsp70 and inhibits α-Synuclein accumulation in pheochromocytoma PC12 cells

Wang

Tang

Jiang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Hsp70 regulates α-Synuclein (α-Syn) degeneration in Parkinson's disease (PD), indicating that Hsp70 promotion may be able to prevent or reverse α-Syn-induced toxicity in PD. Additionally, it has been demonstrated that glutamine (Gln) enhances Hsp70 expression. In the present study, Gln-induced Hsp70 promotion in pheochromocytoma was investigated with reverse transcription-quantitative polymerase chain reaction and western blotting methods. Then it was observed whether heat shock factor (HSF)-1 was required for this phenomenon with an RNA interference strategy. The regulatory role of Gln on α-Syn degeneration was also determined in the α-Syn-overexpressed PC12 [PC12 (α-Syn+)] cells, which were treated with or without the proteasomal inhibitor lactacystin (Lac). The results demonstrated that treatment with ≥10 mM Gln significantly increased Hsp70 mRNA and protein levels (P<0.05) and that this promotion was HSF-1-dependent, as HSF-1 knockout with HSF-1-specific small interfering RNA abrogated Hsp70 promotion in PC12 (α-Syn+) cells. Furthermore, Gln treatment markedly upregulated α-Syn degeneration in PC12 (α-Syn+) cells, which was significantly reduced (P<0.05) in the presence of Lac. Therefore, the present study suggests that Gln is able to induce the promotion of Hsp70 expression in PC12 cells in an HSF-1-dependent manner and that Gln-mediated Hsp70 promotion may increase α-Syn degradation even in the presence of proteasomal inhibitor. Thus, glutamine may be a potential therapeutic agent to prevent α-Syn aggregation in PD.

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Selective loss of 20S proteasome α-subunits in the substantia nigra pars compacta in Parkinson's disease

Cited by 220 publications

References 19 publications

α-Synuclein Expression Levels Do Not Significantly Affect Proteasome Function and Expression in Mice and Stably Transfected PC12 Cell Lines

α-Synuclein Expression Levels Do Not Significantly Affect Proteasome Function and Expression in Mice and Stably Transfected PC12 Cell Lines

Transcriptome analysis reveals link between proteasomal and mitochondrial pathways in Parkinson’s disease

Glutamine promotes Hsp70 and inhibits α-Synuclein accumulation in pheochromocytoma PC12 cells

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