Synaptic localization of HPCAL4 in neurons : looking for a role of this Ca2+ sensor in the modulation of neuronal function in health and disease

Rett Syndrome (RTT) is a severe neurodevelopmental disorder mainly prevalent among females with 1:10.000 births being affected. The main symptoms often begin at around 12–18 months and include arrested cognitive and motor development and loss of acquired verbal skills. Among the neural phenotypes: impairments in neurogenesis, synaptogenesis and abnormal neuronal maturation are the main detrimental defects observed, pointing towards the importance of neuronal signalling in this disorder. Sporadic mutations within the X-linked gene coding for the methyl-CpG binding protein 2 (MeCP2) are the leading cause of the disorder in 90-95% of the patient cases. However, the number of disease-candidate genes has grown over the years with several genes being associated with RTT. Evidence in literature alongside our preliminary results highlighted a clear and robust downregulation of the hippocalcin-like 4 (HPCAL4) mRNA. HPCAL4 belongs to the visinin-like protein family (VSNL), which are involved in the modulation of voltage-gated Ca2+ channels, transcriptional repression, kinase modulation and neuronal calcium signalling. Whether HPCAL4 can be flagged as a modifier gene and a candidate for RTT require further investigations, since little is known about the proper functions beyond its role as calcium sensor. Therefore, we aim to clarify the involvement of HPCAL4 in RTT pathology and its link with the typically observed symptoms and dysfunctions. We explored the spatio-temporal expression of the protein alongside development using RTT mouse models, as well as in vitro cell cultures depicting the disorder, and found that the protein expression is regionally modulated along brain development and is the highest in the hippocampus and cortex. Further, we have initiated analyzing the endogenous expression of the protein in primary hippocampal and cortical neurons and will be elucidating in depth the functional role of this protein by identifying its interactors.