Target generation of cerebellar and striatal neurons as preventive strategy for CNS disorders

Spino-cerebellar ataxias (SCAs) are a collection of genetic diseases characterized by motor incoordination due to neuronal degeneration in the cerebellum. Among the different types of SCAs that have been classified, SCA2 is due to the selective loss of cerebellar projection neurons, the Purkinje cells (PCs). These cells derive from progenitors specified within the cerebellar ventricular neuroepithelium (VN), the major source of cerebellar GABAergic neurons and astrocytes. Here a precise array of microdomains, defined by the expression of specific combinations of transcription factors and proneural genes, generate the different phenotypes according to precise time schedules.

On the other hand, Huntington's disease (HD) represents a dominantly inherited neurodegenerative disorder that affects motor coordination and leads to cognitive decline, dementia and, eventually, death. It is particularly associated, at early phases, to the degeneration of GABAergic medium-spiny neurons (MSNs), the projection neurons of the neostriatum. These cells are specified by progenitors deriving from the embryonic lateral ganglionic eminences (LGE). The striatal primordium derives from successive waves of neural migration that will give rise to the typical mosaic structure of the striatum.

Here we plan to precisely investigate the neurogenic processes in the cerebellar VN and in the LGE. This knowledge will lead us to control the generation of

fate-restricted GABAergic cerebellar and striatal progenitors and to set up preventive cell replacement strategies to treat CNS disorders like SCAs and HD.