The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative diseases affecting mainly children but also adults. NCLs manifest intractable epilepsy, cognitive and motor decline, progressive vision loss, and reduced life expectancy. They have been identified 13 distinct genes (CLN1-8/CLN10-14) and 430 variants. Some gene products are known lysosomal enzymes/proteins, others remain undefined as well as their pathomechanisms. Lysosomal dysfunction is common to all NCLs, typical intracellular autofluorescent aggregates represent pathological hallmarks. CLN8 gene-type diseases show wide complexity due to allelic heterogeneity and different clinical phenotypes: severe late-infantile NCL variants (vLINCL) and a progressive epilepsy with mental retardation (EPMR). The gene product (CLN8p) is an ER-resident transmembrane protein with an ER-ERGIC retrieval signal and a TLC domain likely accounting for lipid sensing/trafficking. Our previous omics studies suggest multiple CLN8p functions , such as vesicular/membrane transport, autophagy, and ceramide/sphigolipids. Consistently, recent evidence by others propose a cargo receptor function for ER-to-Golgi transfer of lysosome enzymes.
- A comprehensive understanding of CLN8p function bringing to a closer definition of the pathomechanism/s.
- Insights into biological basis of CLN8-type genotype/phenotype divergences to design targets of diagnosis and therapy for a direct benefit of CLN8-vLINCL or EMPR patients.
- We are investigating the CLN8p interaction with VAPA, an ER protein working as a docking-site for cytosolic lipid-binding-proteins responsible of ceramide transport, sphingolipid (SL), phospholipid and cholesterol synthesis/trafficking.
- We are also studying defects in autophagy and endosomal-lysosomal pathways.
Patrizia Guarneri Senior Technologist CNR IRIB
Salvatore Papasergi Researcher CNR IRIB
Patrizia Saladino Research fellow
Rosaria Tinnirello Research fellow
Funded by :
- Dipartimento Biotecnologie Mediche e Medicina Traslazionale-Uni. Milano, Alessandro Prinetti
- Sara Grassi
- Laura Mauri
- Paola Giussani
- Simona Prioni
- Anna-Elina Lehesjoki (Folkhälsan Reseach Center di Helsinki-Finland)
- Evren Gumus (Medical Genetics Department)
- Mugla Sitki Kocman (University Turkey)
- Filippo Maria Santorelli (Stella Maris Foundation of Pisa).