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.
Highlights
Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin gene [1]
In this study, that epoxomicin produceed a differential dose-dependent increase in activation of caspase-3 in control and Huntington’s disease (HD) fibroblasts
These results suggested that HD fibroblasts suffered a faster evolution to a senescent phenotype, probably caused by their deficiency in the ubiquitin proteasome system (UPS) activity [21,22,23]
Summary
Huntington’s disease is an autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin gene [1]. Mutant huntingtin accumulates in cells of patients with HD, translocates to the nucleous, alters gene transcription, mitochondrial function and caspase activity and leads to cell death. Besides UPS, another important mechanism to degrade proteins is the autophagy-lysosomal pathway [9,10,11,12]. Both systems are implicated in degradation of abnormal proteins that accumulate in neurodegenerative diseases [10,13,14,15,16,17]
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