PMID- 17341491
OWN - NLM
STAT- MEDLINE
DCOM- 20070828
LR  - 20161124
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 16
IP  - 7
DP  - 2007 Apr 1
TI  - Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 
      is a signal for phagocyte infiltration.
PG  - 837-47
AB  - In the majority of neurodegenerative storage disorders, neuronal death in the 
      brain is followed by infiltration of phagocytic cells (e.g. activated microglia, 
      astroglia and macrophages) for the efficient removal of cell corpses. However, it 
      is increasingly evident that these phagocytes may also cause death of adjoining 
      viable neurons contributing to rapid progression of neurodegeneration. Infantile 
      neuronal ceroid lipofuscinosis (INCL) is a devastating, neurodegenerative, 
      lysosomal storage disorder caused by inactivating mutations in the 
      palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 catalyzes the cleavage of 
      thioester linkages in S-acylated (palmitoylated) proteins and its deficiency 
      leads to abnormal accumulation of thioesterified polypeptides (ceroid) in 
      lysosomes causing INCL pathogenesis. PPT1-knockout (PPT1-KO) mice mimic the 
      clinical and pathological features of human INCL including rapid neuronal death 
      by apoptosis and phagocyte infiltration. We previously reported that in PPT1-KO 
      mice, the neurons undergo endoplasmic reticulum stress activating unfolded 
      protein response, which mediates caspase-12 activation and apoptosis. However, 
      the molecular mechanism(s) by which the phagocytic cells are recruited in the 
      PPT1-KO mouse brain remains poorly understood. We report here that increased 
      production of lysophosphatidylcholine (LPC), catalyzed by the activation of 
      cytosolic phospholipase A(2) (cPLA(2)) in the PPT1-KO mouse brain, is a 'lipid 
      signal' for phagocyte recruitment. We also report that an age-dependent increase 
      in LPC levels in the PPT1-KO mouse brain positively correlates with elevated 
      expression of the genes characteristically associated with phagocytes. We propose 
      that increased cPLA(2)-catalyzed LPC production in the brain is at least one of 
      the mechanisms that mediate phagocyte infiltration contributing to INCL 
      neuropathology.
FAU - Zhang, Zhongjian
AU  - Zhang Z
AD  - Section on Developmental Genetics, Heritable Disorders Branch, National Institute 
      of Child Health and Human Developement, The National Institutes of Health, 
      Bethesda, MD 20892-1830, USA.
FAU - Lee, Yi-Ching
AU  - Lee YC
FAU - Kim, Sung-Jo
AU  - Kim SJ
FAU - Choi, Moonsuk S
AU  - Choi MS
FAU - Tsai, Pei-Chih
AU  - Tsai PC
FAU - Saha, Arjun
AU  - Saha A
FAU - Wei, Hui
AU  - Wei H
FAU - Xu, Yan
AU  - Xu Y
FAU - Xiao, Yi-Jin
AU  - Xiao YJ
FAU - Zhang, Peng
AU  - Zhang P
FAU - Heffer, Alison
AU  - Heffer A
FAU - Mukherjee, Anil B
AU  - Mukherjee AB
LA  - eng
GR  - R01-CA89228/CA/NCI NIH HHS/United States
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20070306
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Galectins)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Lysophosphatidylcholines)
RN  - EC 3.1.1.32 (Phospholipases A)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Brain/*metabolism/ultrastructure
MH  - Cell Movement
MH  - Enzyme Activation
MH  - Galectins/metabolism
MH  - Gene Expression
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Lipid Metabolism/physiology
MH  - Lysophosphatidylcholines/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Microscopy, Electron, Transmission
MH  - Models, Biological
MH  - Phagocytes/cytology/*metabolism
MH  - Phospholipases A/*metabolism
MH  - Polymerase Chain Reaction
MH  - Signal Transduction
MH  - Spectrometry, Mass, Electrospray Ionization
MH  - Thiolester Hydrolases/*genetics
MH  - Time Factors
EDAT- 2007/03/08 09:00
MHDA- 2007/08/29 09:00
CRDT- 2007/03/08 09:00
PHST- 2007/03/08 09:00 [pubmed]
PHST- 2007/08/29 09:00 [medline]
PHST- 2007/03/08 09:00 [entrez]
AID - ddm029 [pii]
AID - 10.1093/hmg/ddm029 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2007 Apr 1;16(7):837-47. doi: 10.1093/hmg/ddm029. Epub 2007 Mar 6.