title: Trehalose improves human fibroblast deficits in a new CHIP-mutation related ataxia.
abstract: 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.
authors.affiliation: Department of Neurobiology, Hospital Ramón y Cajal, Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Casarejos
authors.affiliation: Department of Neurobiology, Hospital Ramón y Cajal, Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Perucho
authors.affiliation: Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: López-Sendón
authors.affiliation: Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Justo
authors.initials: J
authors.lastname: García de Yébenes
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom; Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal; Center of Research in Natural Resources (CIRN) and Department of Biology, University of the Azores, Ponta Delgada, Portugal.
authors.forename: Conceição
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Department of Neurobiology, Hospital Ramón y Cajal, Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gómez
authors.affiliation: Department of Neurology, Hospital Ramón y Cajal, Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ruiz
authors.affiliation: German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rizzu
authors.affiliation: Department of Neurobiology, Hospital Ramón y Cajal, Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Mena
mesh_terms: D001259:Ataxia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D001343:Autophagy; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014199:Trehalose / Q000494:pharmacology* / Q000627:therapeutic use; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D005609:Free Radicals; D018832:Molecular Chaperones; D009842:Oligopeptides; D017382:Reactive Oxygen Species; D014452:Ubiquitins; D014199:Trehalose; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; D053148:Caspase 3; D005978:Glutathione; C078846:epoxomicin