Defining VPS13D’s function(s) to reveal the pathogenetic mechanism causing VPS13D-linked movement disorders

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

It was recently found that patients with mutations in a gene called VPS13D develop a severe condition characterized by motor symptoms of variable nature, including loss of balance and motor coordination, involuntary muscle contractions and prolonged muscle stiffness. These symptoms are caused by the death of brain cells that control movements. However, the almost complete absence of information on VPS13D’s function hampers our understanding of the mechanisms underlying this disease and thus prevents the design of an appropriate cure.

This project aims at investigating features of VPS13D that will reveal its function(s) and at uncovering the pathogenesis of VPS13D-associated disease by observing the effects of VPS13D mutations on brain cells cultured in the lab.

Few studies, including some that I personally contributed to, provided some hints on what VPS13D’ role might be. These studies found that members of the VPS13 family, sharing structural properties with VPS13D, work as channels that allow a fast exchange of lipids (basic components of our cells) between adjacent cellular compartments. One of such compartments, called mitochondrion, is the powerhouse of our cells and disruptions of its integrity is known to be detrimental for cells, especially brain cells. Importantly, damage to the mitochondria and defects in their quality control process have been observed as a consequence of VPS13D mutations. For this reason, we designed experiments to evaluate how VPS13D contributes to mitochondrial integrity and to processes ensuring their quality control. We will observe the changes occurring in mitochondria upon VPS13D mutations or removal, test the importance of VPS13D-mediated lipid exchange, and identify the compartments involved in such exchange.

The information provided by these studies will shed light on VPS13D’s function and on the pathogenetic pathway leading from its mutations to the death of brain cells that ultimately cause VPS13D-associated motor symptoms.