Age-dependent protein modifications and declining proteasome activity in the human lens

Viteri, Gabriela; Carrard, Géraldine; Birlouez‐Aragon, Inès; Silva, Eduardo; Friguet, Bertrand

doi:10.1016/j.abb.2004.05.006

Cited by 85 publications

(34 citation statements)

References 33 publications

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“…More recently, an increased load of modifications by the lipid peroxidation product 4-hydroxy-2-nonenal and the glycoxidation adduct carboxymethyllysine, for specific 20S proteasome subunits was found associated with the age-related decline of 26S proteasome chymotrypsin-like activity purified from human peripheral blood lymphocytes [32]. Increased modification of proteasome b-subunits by 4-hydroxy-2-nonenal was also reported to be associated with decreased proteasome activity in the spinal cord of aged rats [37], while an age-related increased modification of the proteasome by glycoxidation was observed in human lens [42]. In addition to increased modification of proteasome with age, a decreased proteasome subunit expression has been documented in human keratinocytes, human fibroblasts, rat cardiomyocytes and rat spinal cord [31,34,37,39].…”

Section: Impaired Removal Of Oxidized Proteins During Ageingmentioning

confidence: 89%

“…Such a decline of proteasome activity would therefore be expected to promote the accumulation of oxidized protein with age. Indeed, as first shown by us for the peptidylglutamyl peptide hydrolase activity of proteasome purified from rat liver [30], an age-related decrease of at least certain proteasome peptidase activities, has been since reported for human keratinocytes, human fibroblasts, human eye lens, human lymphocytes, rat liver, rat cardiomycytes, rat brain and rat skeletal muscle [31][32][33][34][35][36][37][38][39][40][41][42]. Our initial finding of decreased peptidylglutamyl peptide hydrolase activity of proteasome purified from the liver of old rats was in favor of its specific inactivation.…”

Section: Impaired Removal Of Oxidized Proteins During Ageingmentioning

confidence: 99%

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Oxidized protein degradation and repair in ageing and oxidative stress

2006

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Cellular ageing is characterized by the accumulation of oxidatively modified proteins which may be due to increased protein damage and/or decreased elimination of oxidized protein.Since the proteasome is in charge of protein turnover and removal of oxidized protein, its fate during ageing and upon oxidative stress has received special attention, and evidence has been provided for an age-related impairment of proteasome function. However, proteins when oxidized at the level of sulfur-containing amino acids can also be repaired. Therefore, the fate of the methionine sulfoxide reductase system during ageing has also been addressed as well as its role in protection against oxidative stress.

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Section: Impaired Removal Of Oxidized Proteins During Ageingmentioning

confidence: 89%

Section: Impaired Removal Of Oxidized Proteins During Ageingmentioning

confidence: 99%

Oxidized protein degradation and repair in ageing and oxidative stress

2006

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“…Although the exact mechanism for an age-specific role of proteasomes is unclear, there is a preponderance of evidence that the aging process reduces proteasomal activity in a wide range of tissues. [32][33][34][35][36][37] It is possible that PCa in younger men, who have more proteasomal activity, remains dependent on proteasomes for essential cellular functions and so can be successfully targeted. In older men, cancer cells may have adapted to lower proteasomal activity, and thus are less affected by proteasomal inhibition.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Transcriptomic Analysis Nominates Proteasomal Genes As Age Specific Biomarkers and Therapeutic Targets in Prostate Cancer

Zhao

Jackson

Kothari

et al. 2015

International Journal of Radiation Oncology*Biology*Physics

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BACKGROUND: Although prostate cancer (PCa) is hypothesized to differ in nature between younger versus older patients, the underlying molecular distinctions are poorly understood. We hypothesized that high-throughput transcriptomic analysis would elucidate biological differences in PCas arising in younger versus older men, and would nominate potential age-specific biomarkers and therapeutic targets. METHODS: The high-density Affymetrix GeneChip platform, encompassing 41 million genomic loci, was utilized to assess gene expression in 1090 radical prostatectomy samples from patients with long-term follow-up. We identified genes associated with metastatic progression by 10 years post-treatment in younger (ageo65) versus older (age ⩾ 65) patients, and ranked these genes by their prognostic value. We performed Gene Set Enrichment Analysis (GSEA) to nominate biological concepts that demonstrated agespecific effects, and validated a target by treating with a clinically available drug in three PCa cell lines derived from younger men. RESULTS: Over 80% of the top 1000 prognostic genes in younger and older men were specific to that age group. GSEA nominated the proteasome pathway as the most differentially prognostic in younger versus older patients. High expression of proteasomal genes conferred worse prognosis in younger but not older men on univariate and multivariate analysis. Bortezomib, a Food and Drug Administration approved proteasome inhibitor, decreased proliferation in three PCa cell lines derived from younger patients. CONCLUSIONS: Our data show significant global differences in prognostic genes between older versus younger men. We nominate proteasomeal gene expression as an age-specific biomarker and potential therapeutic target specifically in younger men. Limitations of our study include clinical differences between cohorts, and increased comorbidities and lower survival in older patients. These intriguing findings suggest that current models of PCa biology do not adequately represent genetic heterogeneity of PCa related to age, and future clinical trials would benefit from stratification based on age.

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“…Proteasomes and ubiquitin systems in the lens are involved in the removal of oxidized proteins or peptides (35,36). Despite this, truncated proteins/short peptides might accumulate in the lens because of their excessive production or because the degradation system cannot break down the fragments (37)(38)(39)(40). Earlier studies showed that the lens contains significant quantities of crystallin fragments (6,26), and the complex formed by the interaction of crystallin peptides with proteins in vivo can be modified further to form covalent multimers (5).…”

Section: Discussionmentioning

confidence: 99%

“…An explanation for their accumulation may be that, upon interaction with crystallins, peptides are not accessible to the peptidases that degrade them. The loss of peptidase activity in aged and cataract lenses could also lead to the accumulation of peptides (19,40). The aggregation-influencing activity of peptides seems to be sequence-specific and lost almost completely when hydrophobic residues are replaced with neutral or charged residues.…”

Section: Discussionmentioning

confidence: 99%

Significance of Interactions of Low Molecular Weight Crystallin Fragments in Lens Aging and Cataract Formation

Santhoshkumar

Udupa

Raju

et al. 2008

Journal of Biological Chemistry

110

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Analysis of aged and cataract lenses shows the presence of increased amounts of crystallin fragments in the high molecular weight aggregates of water-soluble and water-insoluble fractions. However, the significance of accumulation and interaction of low molecular weight crystallin fragments in aging and cataract development is not clearly understood. In this study, 23 low molecular mass (<3.5-kDa) peptides in the urea-soluble fractions of young, aged, and aged cataract human lenses were identified by mass spectroscopy. Two peptides, ␣B-(1-18) (MDIAIHHPWIRRPFFPFH) and ␤A3/A1-(59 -74) (SD(N)AYHIERLMSFRPIC), present in aged and cataract lens but not young lens, and a third peptide, ␥S-(167-178) (SPAVQSFRRIVE) present in all three lens groups were synthesized to study the effects of interaction of these peptides with intact ␣-, ␤-, and ␥-crystallins and alcohol dehydrogenase, a protein used in aggregation studies. Interaction of ␣B-(1-18) and ␤A3/A1-(59 -74) peptides increased the scattering of light by ␤-and ␥-crystallin and alcohol dehydrogenase. The ability of ␣-crystallin subunits to function as molecular chaperones was significantly reduced by interaction with ␣B-(1-18) and ␤A3/ A1-(59 -74) peptides, whereas ␥S peptide had no effect on chaperone-like activity of ␣-crystallin. The ␤A3/A1-(59 -74 peptide caused a 5.64-fold increase in ␣B-crystallin oligomeric mass and partial precipitation. Replacing hydrophobic residues in ␣B-(1-18) and ␤A3/A1-(59 -74) peptides abolished their ability to induce crystallin aggregation and light scattering. Our study suggests that interaction of crystallin-derived peptides with intact crystallins could be a key event in age-related protein aggregation in lens and cataractogenesis.

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Age-dependent protein modifications and declining proteasome activity in the human lens

Cited by 85 publications

References 33 publications

Oxidized protein degradation and repair in ageing and oxidative stress

Oxidized protein degradation and repair in ageing and oxidative stress

High-Throughput Transcriptomic Analysis Nominates Proteasomal Genes As Age Specific Biomarkers and Therapeutic Targets in Prostate Cancer

Significance of Interactions of Low Molecular Weight Crystallin Fragments in Lens Aging and Cataract Formation

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