Deciphering the role of Hpcal4 : a potential target for Rett Syndrome ?

Rett Syndrome (RTT) is a severe neurodevelopmental disorder and the leading cause of intellectual disability in females with 1 in 10000 births being affected. The symptoms start to manifest in between 6 and 18 months of age and these include intellectual disability, epilepsy and impairments of social and motor skills. The Mecp2 gene is the main genetic driver behind this disorder; it encodes for the methyl-CpG binding protein 2 (MeCP2), an important epigenetic regulator that is highly enriched in the brain. In fact, mutations within this gene are responsible for impairment of fundamental aspects of neuronal development and function. Previous efforts in the laboratory in accordance with literature highlighted a consistent downregulation of the gene encoding the Hippocalcin-like 4 (HPCAL4) in the brain of RTT mouse models and neuronal cultures depicting the disorder. The protein belongs to a family of neuronal calcium sensors, the visinin-like proteins (VSNLs) that are involved in calcium-dependent signal transduction processes such as neurotransmitter release and modulation of ion channel function. These proteins use the calcium–myristoyl switch mechanism which facilitates binding to membranes and mediates interaction with other proteins. Beyond its involvement in calcium signalling, Hpcal4 function isn’t properly documented. We aim to investigate the role of this calcium sensor and its contribution to neuronal function and potentially clarify its link with RTT. We have assessed its protein expression and found that it is regionally modulated alongside brain development and is reduced in the RTT in vitro and in vivo models. We determined that the protein is enriched in the pre-synaptic compartment and translocates to the membrane following physiological stimulus. We have identified several interactor proteins that have distinct functions related to neurotransmission and clathrin-mediated endocytosis. With these findings and future work focused on investigating the phenotypical and physiological outcomes of Hpcal4 downregulation in neurons, we will obtain a clearer idea on its endogenous role and its potential association with RTT pathophysiology.