Interaction of TBC1D24 with v-ATPase: pathophysiological mechanisms and novel therapeutic targets for rare TBC1D24 diseases

Variants in the TBC1D24 gene are linked to a range of neurodevelopmental disorders, including epilepsy, movement disorders, and deafness. Many of these variants lead to a loss of function in the TBC1D24 protein, resulting in early onset seizures that are often resistant to medications. Our research focuses on understanding how the loss of TBC1D24 function causes seizures and finding new treatments. The TBC1D24 protein has two important domains that play roles in brain cell function and stress resistance. It helps regulate nerve cell development and communication. However, recent evidence suggests that when TBC1D24 doesn't work properly, it can disrupt the balance of acid concentration in the cells. Our project aims to link these acid imbalances with the hyperactivity of brain cells and use small compounds to restore the balance and reduce seizure. We will use cellular and animal preclinical models. In the first part of our study, we will examine how acid levels within cells affect brain cell activity. We will measure electrical activity from brain cells and observe changes in key proteins and processes related to cell health and communication. In the second part, we will test two small compounds, that can adjust acid levels in cells, and assess their ability to restore normal brain cell activity and reduce seizures in our models. The expected outcome of this project is to identify new treatment strategies that can help patients with TBC1D24-related disorders. Our findings may also provide insights into treating other neurodevelopmental conditions that share similar underlying problems