Molecular and functional investigation of the role of TMEM151A in the pathogenesis of paroxysmal disorders

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

The Paroxysmal Kinesigenic Dyskinesia is a genetic movement disorder characterised by brief and frequent attacks of uncontrolled movements caused by frights or sudden voluntary movements. The high frequency of these crisis makes this disease extremely impactful on the quality of life of patients, mostly children and adolescents.

In the last year, mutations in the TMEM151A gene have been shown to cause this condition, often associated with childhood convulsions. Today, we have no knowledge about the TMEM151A gene encoded protein, other than that it is localised in the brain. The research groups (University of Genova) have long experience with paroxysmal disorders which has led to an understanding of the function of the PRRT2 protein in the brain, which is also involved in these disorders.

This project aims to identify the role of TMEM151A in the brain from both a physiological and pathological point of view. We will investigate the localisation of TMEM151A from macro-areas of the brain down to the sub-cellular level, and subsequently its molecular partners. These findings will allow us to understand 'where' and 'with whom' our protein acts, which are fundamental requirements for defining 'how'. The latter aspect will be investigated by assessing neuronal activity in the absence of TMEM151A. We will simulate the pathology using a state-of-the-art technique, allowing us to directly study human neurons in which we have inserted the mutations identified in patients. This knowledge will be crucial in identifying new drug therapies that will improve the quality of life of young patients.