Generation of Striatal Neurons from Mouse and Human Embryonic Stem Cells: its Relevance for Regenerative Medicine in Huntington's Disease and for Studying Striatal Development

Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disorder that usually onsets in midlife. It is characterized by motor, cognitive, and psychiatric symptoms. Once symptomatic, patients are rapidly disabled and require increasing multidisciplinary care. HD is a tremendous burden for medical, social, and family resources. The symptoms and the progression of HD can be linked to its neuropathology, which is characterized by loss of specific neuronal populations in many brain regions. The most important and best studied neuropathology is found in the basal ganglia, in particular a gross atrophy of the striatum. The striatum is characterized by different neuronal populations. Several studies have shown that medium spiny neurons (MSN) are severely affected in HD. MSN are inhibitory projection neurons and are the primary source of stratial projections. Existing medical strategies are available to alleviate some symptoms of HD, including symptomatic therapies (for movements disorders, cognitive impairment, and behavioural manifestations), neuro-protective therapies (anti-glutamatergic drugs), and preventive therapies (for anticipating the clinical onset). Nevertheless, it remains clear that the progressive neurodegenerative process is essentially untreatable medically. For this reason new regenerative therapies that replace neuronal populations and restore function are of great interest and a mandatory research field. This proposal aims at developing new strategies for producing fully functional human striatal neurons from hES with the goal of a future transplantation in HD.