MeCP2 phosphorylation and related kinases in Rett syndrome and early infantile epileptic encephalopathy 2

Rett syndrome (RTT) is a severe genetic disease that because of its incidence is considered the second cause of mental retardation in females; it is characterized by the absence of speech, hand usage, autistic traits and epilepsy. To cure RTT only symptomatic treatments are available. Using a RTT mouse model it has been demonstrated that neurons are not irreversibly damaged and symptoms might therefore be cured. Although these studies do not suggest an immediate therapeutic approach, they demonstrate that a better understanding of the pathophysiologic processes leading to RTT might help developing therapeutic strategies. The design of beneficial remedies requires the disclosure of proteins that regulate the activities of MeCP2, the protein most frequently mutated in RTT, and might be pharmacologically modulated to suppress MeCP2 dysfunctions. This is the purpose of our proposal. We will describe the role in healthy and RTT brains of two proteins (CDKL5 and HIPK2) that we have recently identified as MeCP2 regulators. We know that mutations in CDKL5 cause mental retardation and epilepsy, probably because it associates with MeCP2. With this proposal we will analyze how CDKL5 influences MeCP2 activities and its biological roles in brain. To this purpose we will interfere with CDKL5 expression by specific depletion strategies in neurons and in mouse embryos. Regarding HIPK2, we have very recently discovered that this kinase phosphorylates MeCP2 at serine residue 80, one of the two sites found constitutively phoshorylated in brain. Thus, we will study whether HIPK2 is at least one of the main factors responsible for this MeCP2 modification. Eventually, we will study the role of this phosphorylation in the binding of MeCP2 to specific genes and in the neuronal function. These studies will be instrumental to reveal how mutations in CDKL5 or MeCP2 cause mental retardation and, hopefully, to develop future therapeutic approaches for RTT and related disorders.