HUNTINGTIN FUNCTION AND DYSFUNCTION IN HUNTINGTON’S DISEASE

Huntington’s Disease (HD) is a genetic disease that has a strong impact on families since the mutant gene may be passed on to children, it hits in middle life (mean age is 35 years) and is fatal after 15-20 years of progressive neurodegeneration. No cures are currently available. Telethon's mission is the precise assessment of disease mechanisms since this is the only route to effective cures for genetic diseases. The mutation that causes HD is an abnormal repetition of three nucleotides in a gene encoding for huntingtin. While healthy individuals have a normal huntingtin protein, HD patients suffer from the presence of mutant huntingtin. Research on HD has focused thus far on mutant huntingtin, thereby leading to clinical and genetic findings that define HD as a gain of function disease (i.e. when huntingtin is mutated it acquires a new function that is toxic to striatal cells). More recently, we examined the possibility that HD may also result from the loss of normal huntingtin function. Understanding whether this is indeed true may define new routes and ideas for therapeutic interventions. In addition to the development of drugs that would interfere with the gain of function, one may imagine the development of drugs that will restore normal huntingtin activity. We therefore investigated whether and how normal huntingtin is beneficial to the striatal neurons that die in the disease. We found that normal huntingtin controls the production of Brain-Derived Neurotrophic Factor (BDNF), a critical survival factor for striatal neurons. This effect is lost in HD, since huntingtin is mutated, thereby leading to a reduction in the supply of cortical BDNF to the striatum. Delivery of BDNF to patients may therefore be of interest. Furthermore, the new studies proposed will lead to the definition of the precise mechanisms by which normal huntingtin controls BDNF production and whether and how cortical BDNF dysfunction may further impair neuronal circuitries in HD.