Modulation of ADAM10 at the pre- and post-synaptic terminal and its contribution in Huntington’s Disease cortico-striatal dysfunction

Huntington's disease is a genetic brain disease characterized by the dysfunction of the cortico-striatal circuitry, one of the most important circuits of the brain. Identifying drugs that restore its proper function is one of the main objectives of researchers working in this field. It is known that the selective expression of the mutant huntingtin protein in cortical neurons alters the functionality of the circuit and the healthy status of striatal neurons. The "cortical damage" induced by the mutant toxic protein is therefore sufficient to trigger the pathology. This project focuses on ADAM10, enzyme critical for the synapse. Its activity aberrantly increases in the Huntington brain causing synaptic damage. Our hypothesis is that the increased activity of the enzyme is particularly harmful in the cortex.  We will reconstruct in vitro the cortico-striatal circuit and, by administering an enzyme inhibitor selectively in cortical neurons, we will evaluate whether this treatment is able to prevent defects of the whole circuitry and pathology parameters typically observed in striatal neurons.  This will allow us to understand if ADAM10 is a molecule implicated in cortical damage observed in Huntington's disease. If this were the case, new therapeutic strategies specifically directed on the cortex and based on ADAM10 inhibition could be proposed for the treatment of synaptic defects.