Trehalose reverses cell malfunction in fibroblasts from normal and Huntington's disease patients caused by proteosome inhibition

• Published in: PloS one 2014-02, Vol.9 (2), p.e90202
• Main Authors: Fernandez-Estevez, Maria Angeles, Casarejos, Maria Jose, López Sendon, Jose, Garcia Caldentey, Juan, Ruiz, Carolina, Gomez, Ana, Perucho, Juan, de Yebenes, Justo García, Mena, Maria Angeles
• Format: Article
• Language: English
• Subjects: Abnormalities; Analysis; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Biodegradation; Biology; Biopsy; Caspase; Caspase-3; Cell death; Cell Survival - drug effects; Cognitive ability; Dopamine; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - pathology; Heat shock proteins; High definition television; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Huntingtin; Huntington Disease - chemically induced; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington Disease - prevention & control; Huntington's disease; Huntingtons disease; Kinases; Medical research; Medicine; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neostriatum; Nervous system diseases; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neurology; Neurosciences; Oligopeptides - adverse effects; Oxidative stress; Oxygen; Patients; Phagocytosis; Polyglutamine; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - adverse effects; Proteasomes; Proteins; Proteolysis; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Skin; Trehalose; Trehalose - pharmacology; Trinucleotide repeat diseases; Ubiquitin; Ubiquitination - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0090202

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.