Targeting Hippocalcin-like protein 4 (HPCAL4) provides new therapeutic opportunities for episodic ataxia type 2 and epileptic encephalopathy 42

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

In this project, we investigate the gene Hippocalcin-like 4 (HPCAL4), which is a so-called Tdark gene because very little is known about it. We know that it is expressed in the brain and that it interacts with and promotes the activity of a protein, CACNA1A, which is critical for communication between nerve cells. Indeed, mutations in CACNA1A underlie many brain disorders, including forms of ataxia, epilepsy, hemiplegic migraine and intellectual disability.

There are currently no gene therapies to repair CACNA1A mutations, also because this is a very large gene with a complex structure. In comparison, HPCAL4 is a much smaller gene with a simpler structure, more suitable for developing therapeutic interventions, especially if aimed at regulating its expression.

Given that HPCAL4 promotes the activity of CACNA1A, we reasoned that it could compensate for mutations that reduce CACNA1A activity.

To test this hypothesis, we will first investigate the interplay between these two genes, since the available information is very limited. We will then evaluate how effective HPCAL4 is in compensating for mutations decreasing CACNA1A activity that induce episodic ataxia type 2 and epileptic encephalopathy 42. We will do this in both mouse and human nerve cells.

The ultimate goal of this project is therefore to assess whether the Tdark gene HPCAL4 is a good molecular target to develop therapeutic strategies for forms of ataxia and epileptic encephalopathy.