Discovery of novel genes involved in Huntington’s Disease pathogenesis

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

Huntington’s disease (HD) is an incurable disease, where some specific areas of the brain degenerate. The patients gradually lose their capacity to move and speak and suffer from severe mental conditions. The cause of HD is a mutation in a gene named HTT leading to the production of an abnormal protein called mutant huntingtin (mHtt).

The human genome contains ~20,000 genes, but we know to some extent the function of only ~65% of them. This is due to the fact that once a gene is shown to be important in HD, for example, several researchers will study this gene further, rather than looking for completely novel genes of unknown function, which could be risky and require more efforts.

We know that mHtt causes HD by acting on some known genes. Such information is crucial for the understanding of HD and for the development of therapies, but we also know that we are missing a large part of the picture. In other words, there might be several genes, among the 35% of unknown function, that could be important for human diseases like HD. Identifying them is not a trivial task. By using stem cells and tools for the manipulation of the genome, we have identified, after 7 years of work, over 100 genes potentially involved in HD. We have performed experiments in stem cells and in two animal models of HD confirming that a fraction of these genes are in fact able to counteract the detrimental effects of mHtt. They are therefore potential therapeutic tools against HD.

Crucially, our approach was not based on previous knowledge, so 97% of the genes we found were never previously linked to HD and, even more strikingly, 15% of them are genes of completely unknown function.

 Our aim is therefore very simple, we intend to study the genes of unknown function that we identified. We will confirm whether they play a role in HD and, for those who do, we will understand how. In so doing we will give them for the first time a function and, at the same time, increase our understanding of HD.