Functional properties, localization and physiopathology of putative glucose transporter SLC45A1 involved in epilepsy and intellectual disability

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022 

Despite representing 2.5% of body mass, the human brain consumes ~20% of the total energy. Glucose is the major energy source and transport to and within the brain is of extreme importance. The polar glucose molecule requires specialized transport proteins to pass the blood brain barrier and to enter into neurons. While most glucose transporters are well studied, very little information is available for a neuronal putative sugar transporter encoded by the SLC45A1 gene. The gene has been partially characterized in 2002, but no follow up studies had been devoted to it. Its importance was shown in 2017 by the discovery that patients affected by intellectual disability (ID), epilepsy and variable neuropsychiatric features from two consanguineous families carried SLC45A1 mutations. Ourproposal aims to fill the gap in knowledge on this understudied protein using a combination of complementary technologies. First, we plan to investigate SL45A1 properties using in vitro functional assays. With this knowledge we will then investigate the impact of several variants described in ID patients and reported in the ClinVar database. In parallel we will determine the expression of the protein in various brain regions hoping to obtain further insight into its physiological role. Finally, hypotheses on the pathophysiological role will be tested in vitro in neuronal cultures from WT and SLC45A1 deficient neurons. The project will shed light on the role of the little understood SLC45A brain sugar transporter. The obtained results  are expected to be of broad significance for general brain metabolism in health and disease.