PMID- 16644870
OWN - NLM
STAT- MEDLINE
DCOM- 20060921
LR  - 20150813
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 15
IP  - 11
DP  - 2006 Jun 1
TI  - Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and 
      neurodegeneration in INCL.
PG  - 1826-34
AB  - Infantile neuronal ceroid lipofuscinosis (INCL), a neurodegenerative storage 
      disorder of childhood, is caused by mutations in the palmitoyl-protein 
      thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in S-acylated 
      (palmitoylated) proteins and its mutation causes abnormal intracellular 
      accumulation of fatty-acylated proteins and peptides leading to INCL 
      pathogenesis. Although apoptosis is the suggested cause of neurodegeneration in 
      INCL, the molecular mechanism(s) of apoptosis remains unclear. Using the 
      PPT1-knockout (PPT1-KO) mice that mimic INCL, we previously reported that one 
      mechanism of apoptosis involves endoplasmic reticulum (ER) stress-induced 
      caspase-12 activation. However, the human caspase-12 gene contains several 
      mutations, which make it functionally inactive. Thus, it has been suggested that 
      human caspase-4 is the counterpart of murine caspase-12. Here we report that in 
      the human INCL brain ER stress-induced activation of unfolded protein response 
      (UPR) mediates caspase-4 and caspase-3 activation and apoptosis. Moreover, we 
      show that the INCL brain contains high level of growth-associated protein-43 
      (GAP-43), which is known to undergo palmitoylation. We also demonstrate that 
      transfection of cultured INCL cells with a green fluorescent protein-GAP-43 cDNA 
      construct shows abnormal localization of this protein in the ER. Further, INCL 
      cells manifest evidence of ER stress and UPR (elevated levels of Grp-78/Bip and 
      GADD153), caspase-4 as well as caspase-3 activation and cleavage of 
      poly(ADP)-ribose polymerase, a compelling sign of apoptosis. Most importantly, we 
      show that inhibition of caspase-4 activity protects INCL cells from undergoing 
      apoptosis. Our results provide insight into at least one of the molecular 
      mechanisms of apoptosis in INCL and may allow the identification of potential 
      targets for therapeutic intervention.
FAU - Kim, Sung-Jo
AU  - Kim SJ
AD  - Section on Developmental Genetics, Heritable Disorders Branch, National Institute 
      of Child Health and Human Development/NIH, Bethesda, MD 20892, USA.
FAU - Zhang, Zhongjian
AU  - Zhang Z
FAU - Hitomi, Emiko
AU  - Hitomi E
FAU - Lee, Yi-Ching
AU  - Lee YC
FAU - Mukherjee, Anil B
AU  - Mukherjee AB
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20060427
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 2.7.1.- (Mitogen-Activated Protein Kinase 13)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - Brain/pathology
MH  - Endoplasmic Reticulum/enzymology/*metabolism
MH  - Enzyme Activation
MH  - Humans
MH  - Mice
MH  - Mice, Knockout
MH  - Mitogen-Activated Protein Kinase 13/*metabolism
MH  - Neurodegenerative Diseases/*pathology
MH  - Neuronal Ceroid-Lipofuscinoses/*enzymology/genetics
MH  - Poly(ADP-ribose) Polymerases/metabolism
EDAT- 2006/04/29 09:00
MHDA- 2006/09/22 09:00
CRDT- 2006/04/29 09:00
PHST- 2006/04/29 09:00 [pubmed]
PHST- 2006/09/22 09:00 [medline]
PHST- 2006/04/29 09:00 [entrez]
AID - ddl105 [pii]
AID - 10.1093/hmg/ddl105 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2006 Jun 1;15(11):1826-34. doi: 10.1093/hmg/ddl105. Epub 2006 Apr 
      27.