DISSECTING THE MOLECULAR FUNCTION OF MUTANT HUNTINGTIN WITH STEM CELLS

Huntington disease (HD) is an autosomal dominant disease characterized by a progressive loss of neurons leading to involuntary movements and dementia. The genetic defect causing the disease is an expansion of a CAG triplet in the Huntingtin (Htt) gene, resulting in the formation of a mutant Htt protein. Several cellular changes are associated with the presence of mutant Htt, such as the formation of aggregates of mutant Htt, increased sensitivity to the neurotransmitter glutamate or impaired function of the mitochondria, the power plants of the cell. Yet, we do not know whether these changes are the cause of HD, or simply consequences of a general impairment in the cellular function. Moreover, a valid therapeutic target for HD has not been identified yet. The aim of this project is to find genes involved in the pathogenesis of HD using stem cells as a model. Pluripotent stem cells (PSCs) can be also easily manipulated in vitro and have the ability to differentiate into any cell type of the body and, in particular, neurons. Moreover, PSCs have been derived from HD patients and showed cellular dysfunctions similar to those found in patients, making them ideal tools to study the pathogenesis of HD. We will use cutting edge technologies to scan the genome in order to identify genes that, together with mutant Htt, promote cellular stress and death. Such genes will therefore represent novel potential therapeutic targets, as inhibition of them should reduce or abolish the toxicity caused by mutant Htt. Therefore, we will test the function of those genes in the pathogenesis of HD using neurons derived from PSCs and in mouse models of HD. Hopefully this project will provide the scientific community with novel potential targets for the treatment of HD.