pH-dependent mechanisms of disease caused by TBC1D24 mutations

Awardee: Dennis Brown

Institution: Massachusetts General Hospital

Grant Amount: $60,000.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

There are several lines of evidence, both from genetics and protein-protein interaction studies that there is an important physiological link between Tbc1d24 and a molecular proton pump, called V-ATPase. The major function of the V-ATPase is to pump acid (in the form of protons) into small vesicles inside the cell, such as synaptic vesicles and lysosomes. A low, acidic pH within these vesicles is required for their normal function, in particular neurotransmitter loading of synaptic vesicle in neurons or degradation of various molecules in lysosomes. In addition, proper pH gradients are required for efficient intracellular vesicle trafficking and recycling of proteins, telling them where to go inside a cell, which is extremely important at neuronal synapses. V-ATPase is not a single protein, but a protein complex, consisting of 13 core proteins, or subunits. While severe mutations in V-ATPase subunit genes causing a loss of protein function are incompatible with life, some mutations result in various diseases and syndromes, including epilepsy, hearing loss and DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures). These diseases are remarkably similar to those caused by mutations in the TBC1D24 gene. We discovered recently that V-ATPase physically binds to Tbc1d24, as well as four other proteins that are structurally similar. They all contain a so-called TLDc conserved domain. We found that some mutations in the TLDc domain of one of these other proteins, called Ncoa7, disrupted its ability to bind to V-ATPase, which inhibited its acid-pumping capacity. Importantly, some of these “inhibitory” mutations correspond to the known pathogenic mutations within the Tbc1d24 protein in affected patients. Therefore, we hypothesize and aim to prove that some TBC1D24 pathogenic mutations destabilize the interaction of Tbc1d24 with V-ATPase, resulting in impaired acidification of vesicles within cells, including neuronal cells. We also plan to study where precisely the Tbc1d24/V-ATPase interaction takes place to better understand which intracellular vesicles are more severely affected by the mutations. This will facilitate the development of new treatment strategies and drugs specifically designed to target (stabilize) Tbc1d24-V-ATPase interactions. The hope is that if we can repair this interaction, it will restore the process (e. g., acidification) or pathways disrupted by at least some of pathogenic mutations in the TBC1D24 gene.

Clinical trial readiness through longitudinal disease reconstruction in TBC1D24-related disorders

Awardee: Jillian McKee

Institution: University of Pennsylvania/ Children's Hospital of Philadelphia

Grant Amount: $26,962.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

The proposed research aims to understand the diverse clinical landscape and create a timeline of the likelihood of different clinical features in TBC1D24-related disorders across the lifespan. Data previously published in the literature and extracted from electronic medical records at our large academic medical center will be combined with medical records obtained from the TBC1D24 Family Foundation. Our goal is to understand the natural history and genetic basis of varying disease courses in TBC1D24-related disorders to improve clinical care. We hypothesize that we can identify previously unknown subgroups, disease trajectories, and medication responses that will allow us to predict patient outcomes more precisely, choose appropriate medical treatment strategies, and inform clinical trial design.

BOOSTING AUTOPHAGY AS A THERAPEUTIC STRATEGY TO TREAT TBC1D24 EPILEPSY

Awardee: Anna Fassio

Institution: University of Genoa

Grant Amount: $103,546.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

TBC1D24 has been described by our group and others to play different roles in the brain, however it is not immediate to translate this knowledge in a therapeutic strategy to treat individuals bearing TBC1D24 mutations. We recently identified a degradative cellular process, named autophagy, to be dysfunctional in neuronal cells upon loss of TBC1D24 function. Autophagy is a multistep process responsible for the removal of superfluous or dysfunctional cell components, and it is essential to guarantee neuronal health. Autophagy can be activated by different compounds, and research on small drugs acting on this process is ongoing both in the field of tumors and neurodegenerative diseases. We hypothesize that the use of these new compounds is effective in reverting the autophagy impairment and ameliorates the epileptic phenotype in TBC1D24 patients.