Grant: CIHR Fellowship

Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders characterized by white matter abnormalities affecting the central nervous system (CNS). The origin of gLEs are mostly unknown. We recently discovered a new mutation in the vacuolar protein sorting 11 (Vps11) gene as a cause of a new gLE syndrome. This proposal aims to describe the physiological role of the protein Vps11 in CNS and molecular mechanisms whereby the pathogenic variant contributes to the development of this neurological disease. Given that Vps11 is an essential component of protein complexes implicated in protein trafficking and degradation (i-e autophagy) within cells, we first intent to investigate the variant effect on those specific functions using in vitro assays and patient-derived cell lines. Then, we will evaluate how it alters Vps11 protein-protein interaction network. Since oligodendrocytes are "white matter-producing cells", we will finally determine the role of Vps11 in their development and functions. Briefly, this study will provide relevant molecular and biochemical data regarding the mechanisms and cellular pathways that are regulating or regulated by Vps11. It is noteworthy that it may also unveil what peculiar processes are related to the disease onset. Moreover, it could also uncover new potential drug target that could be beneficial to cure or moderate the development of this type of gLE and help to understand this group of disorders.