PMID- 16571600
OWN - NLM
STAT- MEDLINE
DCOM- 20061003
LR  - 20181201
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 15
IP  - 10
DP  - 2006 May 15
TI  - Palmitoyl-protein thioesterase-1 deficiency leads to the activation of caspase-9 
      and contributes to rapid neurodegeneration in INCL.
PG  - 1580-6
AB  - The infantile neuronal ceroid lipofuscinosis (INCL), a rare (one in 100 000 
      births) but one of the most lethal inherited neurodegenerative storage disorders 
      of childhood, is caused by inactivating mutations in the palmitoyl-protein 
      thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in s-acylated 
      (palmitoylated) proteins and facilitates their degradation and/or recycling. 
      Thus, PPT1-deficiency leads to an abnormal intracellular accumulation of 
      s-acylated proteins causing INCL pathogenesis. Although neuronal apoptosis is the 
      suggested cause of neurodegeneration in this disease, the molecular mechanism(s) 
      remains poorly understood. We recently reported that one of the major pathways of 
      neuronal apoptosis in PPT1-knockout (PPT1-KO) mice that mimic INCL, is mediated 
      by endoplasmic reticulum (ER) stress-induced caspase-12 activation. ER stress 
      also increases the production of reactive oxygen species (ROS), disrupts Ca(2+) 
      homeostasis and increases the potential for destabilizing mitochondrial membrane. 
      Mitochondrial membrane destabilization activates caspase-9 present in this 
      organelle, and can mediate apoptosis. We report here that the levels of 
      superoxide dismutase (SOD), most likely induced by ROS, in human INCL as well as 
      PPT1-KO mouse brain tissues are markedly elevated. Moreover, we demonstrate that 
      activated caspase-3 and cleaved-PARP, indicative of apoptosis, are also increased 
      in these tissues. Using cultured neurospheres from PPT1-KO and wild-type mouse 
      fetuses, we further demonstrate that the levels of ROS, SOD-2, cleaved-caspase-9, 
      activated caspase-3 and cleaved-PARP are elevated. We propose that: (i) ER stress 
      due to PPT1-deficiency increases ROS and disrupts calcium homeostasis activating 
      caspase-9 and (ii) caspase-9 activation mediates caspase-3 activation and 
      apoptosis contributing to rapid neurodegeneration in INCL.
FAU - Kim, Sung-Jo
AU  - Kim SJ
AD  - Section on Developmental Genetics, Heritable Disorders Branch, National Institute 
      of Child Health and Human Development, National Institutes of Health, Bethesda, 
      Maryland 20892-1830, USA.
FAU - Zhang, Zhongjian
AU  - Zhang Z
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 - 20060328
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (COL11A2 protein, human)
RN  - 0 (Collagen Type XI)
RN  - 0 (Membrane Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 1.15.1.1 (superoxide dismutase 2)
RN  - EC 2.4.2.30 (Parp1 protein, mouse)
RN  - EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
RN  - EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (PPT1 protein, human)
RN  - EC 3.4.22.- (CASP3 protein, human)
RN  - EC 3.4.22.- (CASP9 protein, human)
RN  - EC 3.4.22.- (Casp3 protein, mouse)
RN  - EC 3.4.22.- (Casp9 protein, mouse)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspase 9)
RN  - EC 3.4.22.- (Caspases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Apoptosis/*physiology
MH  - Brain/abnormalities/metabolism
MH  - Calcium/metabolism
MH  - Caspase 3
MH  - Caspase 9
MH  - Caspases/*metabolism
MH  - Cells, Cultured
MH  - Collagen Type XI/metabolism
MH  - Endoplasmic Reticulum/metabolism
MH  - Enzyme Activation
MH  - Humans
MH  - Membrane Proteins/*deficiency
MH  - Mice
MH  - Mice, Knockout
MH  - Nerve Degeneration/*pathology
MH  - Neuronal Ceroid-Lipofuscinoses/embryology/enzymology/*pathology
MH  - Poly (ADP-Ribose) Polymerase-1
MH  - Poly(ADP-ribose) Polymerases/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Superoxide Dismutase/metabolism
MH  - Thiolester Hydrolases
EDAT- 2006/03/31 09:00
MHDA- 2006/10/04 09:00
CRDT- 2006/03/31 09:00
PHST- 2006/03/31 09:00 [pubmed]
PHST- 2006/10/04 09:00 [medline]
PHST- 2006/03/31 09:00 [entrez]
AID - ddl078 [pii]
AID - 10.1093/hmg/ddl078 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2006 May 15;15(10):1580-6. doi: 10.1093/hmg/ddl078. Epub 2006 Mar 
      28.