The main interest of the autophagy-related diseases group is the study of genetic diseases associated with defects in autophagy. Autophagy is an intracellular degradation mechanism essential for cell survival under starvation conditions and maintenance of organelle homeostasis, and its dysfunction is directly related to several rare diseases. Macroautophagy, the best characterized autophagy pathway, consists of the formation of a double membrane vesicle in the cytosol called autophagosome, that engulfs the cargo and then fuses with lysosomes where its degradation takes place. Our main goal is to understand the molecular mechanism of autophagy and its regulation, which is essential for the use of autophagy as a therapeutic target.
Our laboratory uses different model systems to study autophagy, including the yeast Saccharomyces cerevisiae, the social amoeba Dictyostelium discoideum and mammalian cells in culture. Our multidisciplinary approach allows a deep level of analysis of the proteins involved in the mechanism of autophagy with an emphasis in those related to rare diseases. More specifically, we have focused on the study of two gene families, the WIPI and VPS13 families, which are functionally related.
The WIPI gene family
The biogenesis of the autophagosome requires the function of WIPI proteins, a family of proteins involved in several rare diseases including BPAN (beta-propeller protein associated neurodegeneration caused by mutations in WIPI4). The cytopathological basis of BPAN is not fully understood and, although autophagy appears to play an important role, we are studying possible connections with non-canonical autophagy, with autophagosome-lysosome fusion, and with other pathways such as ER stress. WIPI proteins are associated to the lipid transport between the ER and the autophagosome membrane mediated by ATG2, a large tubular protein containing a hydrophobic cavity responsible for the transfer of lipids between membranes. The function of the scramblases ATG9 and VMP1 are also required to stabilize the lipid bilayers.
The VPS13 gene family
In addition to ATG2, there are other intermembrane lipid transfer proteins with similar structure, the VPS13 proteins. This very large protein was initially characterized in yeast as a protein involved in several apparently unrelated processes such as endosome-Golgi trafficking, mitochondrial integrity and prospore membrane formation. Subsequently, it was shown that several adaptors localize Vps13 to different organelles and that this protein plays a similar role as Atg2 and transfer lipids at different membrane contact sites (MCS). The human genome encodes four VPS13 proteins (A-D). Mutations in VPS13A causes ChAc (Chorea-acanthocytosos), a disease also associated with autophagy defects. We are pursuing the identification of the determinants and the adaptors involved in localization of the mammalian VPS13 protein at specific MCS, a molecular aspect that is essential to understand the cytopathological consequences of their mutations.