Trehalose improves human fibroblast deficits in a new CHIP-mutation related ataxia
| Autor: | Ana Gómez, María José Casarejos, Conceição Bettencourt, Jose Lopez-Sendon, Justo García de Yébenes, Juan Perucho, Maria Angeles Mena, Carolina Ruiz, Peter Heutink, Patrizia Rizzu |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Physiology
lcsh:Medicine Gene Expression metabolism [Free Radicals] chemistry.chemical_compound Chaperone-mediated autophagy Molecular Cell Biology Medicine and Health Sciences Homeostasis metabolism [Reactive Oxygen Species] lcsh:Science metabolism [Molecular Chaperones] Cells Cultured Cellular Stress Responses genetics [Ubiquitin-Protein Ligases] Multidisciplinary LAMP2 Movement Disorders Caspase 3 pharmacology [Oligopeptides] Neurodegenerative Diseases genetics [Ataxia] Glutathione Cell biology Mitochondria metabolism [Ubiquitins] Neurology Cell Processes epoxomicin metabolism [Glutathione] metabolism [Ataxia] Oligopeptides metabolism [Fibroblasts] Research Article Programmed cell death Free Radicals Cell Survival drug effects [Cell Survival] Ubiquitin-Protein Ligases Biology Epoxomicin drug therapy [Ataxia] pharmacology [Trehalose] Genetics Autophagy metabolism [Caspase 3] Humans ddc:610 Ubiquitins therapeutic use [Trehalose] Cell Proliferation STUB1 protein human drug effects [Fibroblasts] lcsh:R Biology and Life Sciences Trehalose Cell Biology Fibroblasts metabolism [Mitochondria] Protein ubiquitination Proteostasis chemistry Genetics of Disease Mutation lcsh:Q Ataxia Physiological Processes Reactive Oxygen Species Molecular Chaperones |
| Zdroj: | PLOS ONE 9(9), e106931 (2014). doi:10.1371/journal.pone.0106931 PLoS ONE PLoS ONE, Vol 9, Iss 9, p e106931 (2014) |
| DOI: | 10.1371/journal.pone.0106931 |
| Popis: | In this work we investigate the role of CHIP in a new CHIP-mutation related ataxia and the therapeutic potential of trehalose. The patient's fibroblasts with a new form of hereditary ataxia, related to STUB1 gene (CHIP) mutations, and three age and sex-matched controls were treated with epoxomicin and trehalose. The effects on cell death, protein misfolding and proteostasis were evaluated. Recent studies have revealed that mutations in STUB-1 gene lead to a growing list of molecular defects as deregulation of protein quality, inhibition of proteasome, cell death, decreased autophagy and alteration in CHIP and HSP70 levels. In this CHIP-mutant patient fibroblasts the inhibition of proteasome with epoxomicin induced severe pathophysiological age-associated changes, cell death and protein ubiquitination. Additionally, treatment with epoxomicin produced a dose-dependent increase in the number of cleaved caspase-3 positive cells. However, co-treatment with trehalose, a disaccharide of glucose present in a wide variety of organisms and known as a autophagy enhancer, reduced these pathological events. Trehalose application also increased CHIP and HSP70 expression and GSH free radical levels. Furthermore, trehalose augmented macro and chaperone mediated autophagy (CMA), rising the levels of LC3, LAMP2, CD63 and increasing the expression of Beclin-1 and Atg5-Atg12. Trehalose treatment in addition increased the percentage of immunoreactive cells to HSC70 and LAMP2 and reduced the autophagic substrate, p62. Although this is an individual case based on only one patient and the statistical comparisons are not valid between controls and patient, the low variability among controls and the obvious differences with this patient allow us to conclude that trehalose, through its autophagy activation capacity, anti-aggregation properties, anti-oxidative effects and lack of toxicity, could be very promising for the treatment of CHIP-mutation related ataxia, and possibly a wide spectrum of neurodegenerative disorders related to protein disconformation. |
| Databáze: | OpenAIRE |
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