The interplay between the SNARE protein SNAP29 and the COG tethering complex in physiology and pathology: cellular and organismal studies of Golgi trafficking in Drosophila models of congenital rare diseases

The Golgi complex is a central sorting node in the endomembrane trafficking routes and a biosynthetic and processing center for glycoproteins and lipids. Cargo sorting, trafficking and glycoprotein glycosylation, all require concerted action of vesicular tethers and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-proteins, which control docking and fusion of vesicular transport carriers to acceptor compartments. Mutations that affect such Golgi-based machinery have serious consequences on human health, leading to congenital disorders, neurodegenerative disease and viral infections. Mutations affecting genes encoding subunits of the human tethering COG (Conserved oligomeric Golgi) complex cause monogenic forms of Congenital Disorders of Glycosylation (CDG). Similarly, loss-of-function mutations in the gene encoding the SNARE protein SNAP29 cause Cerebral Dysgenesis, Neuropathy, Ichthyosis, palmoplantar Keratoderma (CEDNIK), a rare autosomal recessive syndrome. Interestingly, CEDNIK shares several clinical aspects with COG-CDG, that include neurological impairment and microcephaly. While the role of the COG complex in facilitating GC trafficking is well established, the activity of SNAP29 in docking and fusion at the GC has been only recently recognized. However, an interaction of SNAP29 with a COG component has been reported but it is not clear whether and how the COG complex and SNAP29 act together at the GC. The overall goal of our project is to investigate molecular mechanisms that involve COG and SNAP29 at the GC in physiology and pathology. To this end, we will use Drosophila melanogaster, a premier model organism in neuroscience. Taking advantage of the superior genetic tools of Drosophila as well as the ease of cell-based in vivo approaches, in our project we will: - investigate the molecular interactions between COG subunits and Snap29 - discover the consequences of impaired COG and Snap29 activity in the Drosophila nervous system - uncover possible links between COG and Snap29 associated diseases We anticipate that our studies will illuminate the connection between altered Golgi trafficking, glycosylation and the clinical manifestations of COG-CDG and CEDNIK and provide valuable knowledge for devising future therapeutic strategies