Identification of therapeutic targets in primary microcephaly through the analysis of the CIT-K/ASPM pathway

Genetic microcephalies are disorders characterized by a strong reduction of the brain volume, often associated with deeply invalidating symptoms, such as intellectual disability, epilepsy, ataxia and paralysis. In the great majority of cases, these syndromes are caused by a reduced production or by a loss of neurons during embryogenesis. Therefore, the development of effective therapies represents one of the hardest frontiers of medicine, especially because every intervention aimed to modify the causal events must be undertaken during pregnancy. A deep understanding of the molecular and of the cellular mechanisms leading to microcephaly is the fundamental pre-requisite for the development of new therapies. During the last decade, the genes responsible for many forms of these disorders have been identified, leading to a strong improvement in diagnosis. However, the molecular mechanisms by which these genes affect brain development are still obscure. In our laboratory we have generated, with the support of Telethon, a mouse line that develops a severe form of microcephaly because of a mutation in the CIT-K gene. In this application we propose to continue our studies on these mice for different reasons deriving from our preliminary studies. First, the CIT-K protein is very likely to cooperate with other microcephaly proteins. Second, CIT-K-deficient mice could e a very interesting general model to study microcephaly, because they show both increased death and, probably, reduced generation of neuronal precursors during embryogenesis. Last, and most important, we obtained strong evidence that the cellular abnormalities that characterize these mice can be significantly reverted through the modulation of proteins that can be targeted by available pharmacological compounds. We think that our research program could significantly extend the understanding of microcephaly and the possibilities to fight them.