Abstract:
Juvenile neuronal ceroid lipofuscinosis (JNCL) belongs to the neuronal ceroid lipofuscinoses characterized by blindness-seizures-motor-cognitive decline and early death. JNCL is caused by CLN3 gene mutations that negatively modulate cell growth-apoptosis. CLN3 protein (CLN3p) localizes to Golgi-Rab4--Rab11-positive endosomes and lipid rafts, and harbors a galactosylceramide (GalCer) lipid raft-binding domain. Goals are proving CLN3p participates in GalCer transport from Golgi to rafts, and GalCer deficits negatively affect cell growth-apoptosis. GalCer-mutant CLN3p are retained in Golgi, with CLN3p rescuing GalCer deficits in rafts. Diminishing GalCer in normal cells by GalCer synthase siRNA negatively affects cell growth-apoptosis. GalCer restores JNCL cell growth. WT CLN3p binds GalCer, but not mutant CLN3p. Sphingolipid content of rafts-Golgi is perturbed with diminished GalCer in rafts and accumulation in Golgi. CLN3-deficient raft vesicular structures are small by transmission electron microscopy, reflecting altered sphingolipid composition of rafts. CLN1-CLN2-CLN6 proteins bind to lysophosphatidic acid-sulfatide, CLN6-CLN8 proteins to GalCer, and CLN8 protein to ceramide. Sphingolipid composition-morphology of CLN1--CLN2--CLN6--CLN8- and CLN9-deficient rafts are altered suggesting changes in raft structure-lipid stoichiometry could be common themes underlying these diseases. Copyright © 2008 International Pediatric Research Foundation, Inc.