title: Trehalose reverses cell malfunction in fibroblasts from normal and Huntington's disease patients caused by proteosome inhibition.
abstract: Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor, cognitive and psychiatric deficits, associated with predominant loss of striatal neurons and is caused by polyglutamine expansion in the huntingtin protein. Mutant huntingtin protein and its fragments are resistant to protein degradation and produce a blockade of the ubiquitin proteasome system (UPS). In HD models, the proteasome inhibitor epoxomicin aggravates protein accumulation and the inductor of autophagy, trehalose, diminishes it. We have investigated the effects of epoxomicin and trehalose in skin fibroblasts of control and HD patients. Untreated HD fibroblasts have increased the levels of ubiquitinized proteins and higher levels of reactive oxygen species (ROS), huntingtin and the autophagy marker LAMP2A. Baseline replication rates were higher in HD than in controls fibroblasts but that was reverted after 12 passages. Epoxomicin increases the activated caspase-3, HSP70, huntingtin, ubiquitinated proteins and ROS levels in both HD and controls. Treatment with trehalose counteracts the increase in ROS, ubiquitinated proteins, huntingtin and activated caspase-3 levels induced by epoxomicin, and also increases the LC3 levels more in HD fibroblast than controls. These results suggest that trehalose could revert protein processing abnormalities in patients with Huntington's Disease.
authors.affiliation: Department of Neurobiology, Ramón y Cajal Hospital, Madrid, Spain ; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Fernandez-Estevez
authors.affiliation: Department of Neurobiology, Ramón y Cajal Hospital, Madrid, Spain ; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Casarejos
authors.affiliation: Department of Neurology, Ramón y Cajal Hospital, Madrid, Spain ; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: López Sendon
authors.affiliation: Department of Neurology, Ramón y Cajal Hospital, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Garcia Caldentey
authors.affiliation: Department of Neurology, Ramón y Cajal Hospital, Madrid, Spain ; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ruiz
authors.affiliation: Department of Neurobiology, Ramón y Cajal Hospital, Madrid, Spain ; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Department of Neurobiology, Ramón y Cajal Hospital, Madrid, Spain ; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Perucho
authors.affiliation: Department of Neurology, Ramón y Cajal Hospital, Madrid, Spain ; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Justo García
authors.initials: JG
authors.lastname: de Yebenes
authors.affiliation: Department of Neurobiology, Ramón y Cajal Hospital, Madrid, Spain ; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Mena
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009842:Oligopeptides / Q000009:adverse effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000009:adverse effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014199:Trehalose / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D018840:HSP70 Heat-Shock Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D014199:Trehalose; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin