Le lipofuscinosi ceroidee neuronali (NCLs) sono un gruppo di malattie neurodegenerative autosomico-recessive appartenenti alla famiglia della patologie a carico lisosomiale, manifeste principalmente nell'infanzia ma associate a variabili genetiche e cliniche (12 gene distinti e 430 mutazioni differenti) . I sintomi comprendono un progressivo deterioramento mentale e motorio, epilessia, atassia, in alcuni casi anche perdita della visione, e ridotta aspettativa di vita. Forme adulte hanno carattere sia dominante che recessivo. Il progetto propone uno studio per definire il ruolo del gene CLN8 implicato in due varianti di NCLs nella sintesi e nel trafficking degli sfingolipidi e caratterizzare l'implicazione della disfunzione degli sfingolipidi nelle forme CLN8-NCLs.
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.
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
Patrizia Guarneri;Salvatore Papasergi;Patrizia Saladino;Irene Deidda;
2017
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
