Huntington´s disease (HD) is a neurodegenerative disease in which a loss of a specific population of striatal neurons, the striatal projection neurons (SPN), is observed. There is no treatment for HD patients and, thus, the development of therapeutic approaches is needed. In addition, the onset definition is controversial: some cognitive symptoms appear 20-40 years before the classical motor alterations. We and others have recently shown embryonic developmental defects in HD models and in human pluripotent stem cells (hPSC) suggesting that a defective neuronal circuitry formation could be responsible for the neuronal loss that occurs in the adult brain. Understanding these developmental alterations and consequences in the adult brain helps to define a therapeutic window for HD. Here, we present a multi-focus design for the characterization of the striatal progenitors during human and mouse embryonic development based on big data analysis from sc/snRNAseq in control and HD samples, sc/sn RNAseq of hPSC differentiated towards SPN, and from hPSC transplanted in mouse.  Our first analysis shows the differential contribution of control versus HD-derived cells to some specific neural progenitor clusters, defined by genes that can be used to track subpopulations of progenitors. In addition, the integration of this data set in a digital model will show the progression of HD. This valuable tool will help to identify key steps in which the first HD neuronal alterations are detected.   

The proposed multidisciplinary approach helps to establish which progenitor subpopulations are altered in HD during development, and, therefore, to define an early putative treatment.