CLN3 defines a novel antiapoptotic pathway operative in neurodegeneration and mediated by ceramide.
Juvenile neuronal ceroid lipofuscinosis or Batten disease (JNCL) is a neurodegenerative disorder characterized by blindness, seizures, cognitive decline and early death. Brain atrophy and retinitis pigmentosa ensue because of neuronal and photoreceptor apoptosis. The CLN3 gene defective in JNCL encodes a novel 438 amino acid protein. Most affected genes harbor a deletion resulting in a truncated protein. CLN3 overexpression in NT2 cells enhances growth, reverses growth inhibition induced by serum starvation and protects from apoptosis induced by vincristine, staurosporine, and etoposide but not from death caused by ceramide. CLN3 modulates endogenous and vincristine-activated ceramide, and therefore suppresses apoptosis by impacting generation of ceramide.
Puranam
K L
KL
Departments of Pediatrics and Neurobiology, Duke University Medical Center, Durham, North Carolina, 27710, USA.
Guo
W X
WX
Qian
W H
WH
Nikbakht
K
K
Boustany
R M
RM
D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D016213:Cyclins; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014750:Vincristine / Q000494:pharmacology
C079895:CLN3 protein, S cerevisiae; C105199:CLN3 protein, human; D002518:Ceramides; D016213:Cyclins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C064769:N-acetylsphingosine; D029701:Saccharomyces cerevisiae Proteins; C101954:N-caproylsphingosine; D014750:Vincristine; D005047:Etoposide; D011065:Poly(ADP-ribose) Polymerases; D019311:Staurosporine; D013110:Sphingosine