Huntington's disease (HD) is a hereditary, fatal neurodegenerative disorder, mainly affecting people in mid-life. Although more than 20 years have passed since the discovery of the disease-causing genetic mutation - an expanded DNA repeat at the tip of chromosome 4 -, the challenge is still to determine which pathways are directly responsible for the pathological process. Although recent efforts aimed to decrease mutant huntingtin protein show promising results, no treatments are available to the clinic to delay or to arrest the disease progression. In order to identify molecular mechanisms driving HD, in this project we investigated how RNA processing could be altered by the HD mutation, specifically in those neurons that are more sensitive to the disease. To answer this question we resourced to the use of “HD mice”, carefully replicating the human mutation, focusing on striatal brain regions that are most vulnerable to HD. We searched for changes presenting more severe alterations with increasing severity in the HD mutation – longer triplet expansion - in a manner that totally recapitulated the human HD mutation. Particularly, through an integrative effort to combine cutting edge methods to visualize, isolate and profile single neurons and analysis of “big, bioinformatic datasets”, we aimed to characterize the molecular sensitizers that render some subpopulation of neurons susceptible to HD mutation. Thanks to the HD genetics criteria utilized – mouse model faithfully replicating the HD mutation, selection of molecular phenotypes based on for severity of the mutation – and the pioneering approach applied, we have every expectation to have identified dysregulated pathways proximal to the mutation, thus likely to more relevant for the disease pathologic process. Thus, the outcome of this project will lead to the discovery of early pathways and networks of genes altered by the mutation and ultimately responsible for neuronal cell death to be targeted or protected in search of new, effective therapeutic treatments.
