Targeting lipids in CLN8-associated NCL diseases: structural and functional interaction of CLN8 with vesicle-associated membrane protein-associated protein A (VAPA), and genotype-phenotype correlations. TELETHON Grant GGP16277

The neuronal ceroid lipofuscinoses (NCLs) are devastating autosomal recessive neurodegenerative diseases of children, belonging to the family of lysosomal storage disorders (LSDs). More rare adult forms are also described and can be present with either dominant or recessive patterns of inheritance. NCLs show broad clinical and allelic heterogeneity, more than twelve genes (CLN genes) and 430 mutations are known, and they are characterized by a common feature of intralysosomal accumulation of lipofuscin/ceroid. Clinical symptoms depend on age at onset and on genetic form, although there are differences and disease subgroups still have unknown molecular genetic backgrounds. In general, children develop progressive mental and motor deterioration, epilepsy, ataxia, in some cases also visual loss, and have reduced life expectancy . The proposal intends to investigate the role of CLN8, which is involved in two variants of NCLs, in sphingolipid synthesis/trafficking. The possibility that CLN8 may function as a sensor of ceramide/sphingolipid levels, as a player in their cellular trafficking and as a regulator in their biosynthetic pathway is an important subject of investigation in that it allows to identify a primary sphingolipid dysfunction-related defect linked to the NCLs' family.