CLN3p impacts galactosylceramide transport, raft morphology, and lipid content

Pediatr Res. 2008 Jun;63(6):625-31. doi: 10.1203/PDR.0b013e31816fdc17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line
  • Cell Proliferation
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism
  • Fibroblasts / metabolism
  • Galactosylceramides / deficiency
  • Galactosylceramides / metabolism*
  • Golgi Apparatus / metabolism
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Lipids / metabolism*
  • Membrane Microdomains / metabolism*
  • Membrane Microdomains / ultrastructure
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / metabolism*
  • Neuronal Ceroid-Lipofuscinoses / pathology
  • Protein Binding
  • Protein Transport
  • Subcellular Fractions
  • Sulfoglycosphingolipids / metabolism
  • Tripeptidyl-Peptidase 1


  • CLN3 protein, human
  • CLN3 protein, mouse
  • Cln8 protein, mouse
  • Galactosylceramides
  • Membrane Glycoproteins
  • Membrane Lipids
  • Membrane Proteins
  • Molecular Chaperones
  • Sulfoglycosphingolipids
  • Tpp1 protein, mouse
  • Tripeptidyl-Peptidase 1
  • TPP1 protein, human