Role of ZDHHC proteins in Early-onset familial autosomal dominant Alzheimer disease

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

Early onset familial Alzheimer's disease (eFAD) is a rare disease that mimics the symptoms of senile dementia but occurs at a very early age (usually between 40 and 50 years). Although some clinical features link eFAD to Alzheimer's disease (AD), researchers are now convinced that these are diseases with different etiopathogenesis. Indeed, while environmental factors and lifestyle play a fundamental role for AD, eFAD is an autosomal dominant genetic disease for which at least three genes responsible for the early onset of neurodegeneration in a significant number of families have been identified. Nonetheless, it is believed that other genes responsible for eFAD are yet to be discovered. Furthermore, to date the few therapeutic tools available for patients with eFAD are not very effective. This basic research project aims to investigate the role of a family of genes encoding S-acyltransferase (zDHHCs) enzymes in the onset and progression of eFAD. The zDHHC enzymes regulate the S-palmitoylation of a number of proteins important for synaptic function in our brain. In experimental models of eFAD, the presence of brain insulin resistance has been demonstrated in a early phase preceding the onset of symptoms. Furthermore, our group has shown that brain insulin resistance can cause an altered expression of zDHHCs enzymes with consequent alteration of protein palmitoylation, impairment of synaptic function and memory deficit. Finally, our experimental evidence indicates that a palmitoylation inhibitor drug, 2-bromopalmitate, is capable to delay the onset and slow the progression of cognitive deficits in an experimental model of eFAD. This project represents the first systematic study on the role of zDHHC enzymes in eFAD