Molecular bases and in vitro modeling of Cdkl5 dependent infantile neurological disorders

Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. Mutations in the MECP2 gene have long represented the only known cause of Rett. Recent studies have identified CDKL5 as the gene responsible for the Rett variant form associated with severe early epileptic crises. In particular, the early-seizure variant is recognized for the absence of an apparent period of normal perinatal development while severe early-onset epileptic seizures are evident soon after birth. Nevertheless, these patients display several of the classical symptoms of Rett syndrome, such as loss of speech, stereotypic hand movements and microcephaly. This particular form of Rett only rarely is associated with MeCP2 mutations while is commonly caused by CDKL5 deficiency. CDKL5 is coding for a kinase protein whose function has been only partially elucidated so far. We contributed in the past to identify CDKL5 as a brain-localized protein active during the process of neuronal maturation and activity. In neurons, CDKL5 is enriched at the synapses. Each single neuron develops hundreds of synapses to contact its neighbors and communicate with them. Correct neuronal activity and related cognitive functions are strictly dependent by the correct functionality of these structures. In particular their dynamic changes in adhesion and activity mediate essential cognitive functions as neuronal plasticity and memory and learning. We will characterize CDKL5 role and its molecular partners in these structures. Moreover, we have established an innovative cellular model of the disease by generating reprogrammed stem cells from the fibroblasts of CDKL5 patients. These fibroblast-derived stem cells will be differentiated into neurons providing a direct access to the human cells whose alterations represent the cause of the disease. This model will accelerate our knowledge on CDKL5 and the establishment of new therapeutic strategies.