Abstract

Huntingtons disease (HD) is a devastating neurodegenerative disorder for which there is no effective treatment yet. The disease presents motor, psychiatric and cognitive symptoms, and it is caused by the expansion of CAG repeats in the huntingtin (htt) gene, which codes for a polyglutamine tract in the htt protein. The repeat expansion causes the preferential degeneration of the medium spiny neurons in the caudate-putamen of patients, and the symptoms of the disease normally appear between the third and the fifth decades of life. Despite important advances in the study of this disease, the mechanism(s) by which the mutated protein induces the degeneration of the striatal neurons remains elusive. Thus, current therapeutic approaches are symptomatic, and directed to relieve specific aspects of the disease, but cannot detain neuronal degeneration, or induce functional recovery. In this review, we will first describe the existing knowledge of the molecular basis of the disease obtained both from the study of patients and from animal models, with particular attention to transgenic models. Finally, we will discuss novel and rational therapies designed to control the transcriptional changes associated with the disease, the apoptotic death of neurons, the alterations of energy metabolism and oxidative damage, and neuroprotective strategies, with a special focus on gene therapy, as well as restorative therapies.

Keywords: huntington disease, neurodegenerative disorder, htt protein, huntingtin (htt) gene