PMID- 16368712
OWN - NLM
STAT- MEDLINE
DCOM- 20060712
LR  - 20150813
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 15
IP  - 2
DP  - 2006 Jan 15
TI  - Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the 
      unfolded protein response and neuronal apoptosis in INCL.
PG  - 337-46
AB  - Numerous proteins undergo modification by palmitic acid (S-acylation) for their 
      biological functions including signal transduction, vesicular transport and 
      maintenance of cellular architecture. Although palmitoylation is an essential 
      modification, these proteins must also undergo depalmitoylation for their 
      degradation by lysosomal proteases. Palmitoyl-protein thioesterase-1 (PPT1), a 
      lysosomal enzyme, cleaves thioester linkages in S-acylated proteins and removes 
      palmitate residues facilitating the degradation of these proteins. Thus, 
      inactivating mutations in the PPT1 gene cause infantile neuronal ceroid 
      lipofuscinosis (INCL), a devastating neurodegenerative storage disorder of 
      childhood. Although rapidly progressing brain atrophy is the most dramatic 
      pathological manifestation of INCL, the molecular mechanism(s) remains unclear. 
      Using PPT1-knockout (PPT1-KO) mice that mimic human INCL, we report here that the 
      endoplasmic reticulum (ER) in the brain cells of these mice is structurally 
      abnormal. Further, we demonstrate that the level of growth-associated protein-43 
      (GAP-43), a palmitoylated neuronal protein, is elevated in the brains of PPT1-KO 
      mice. Moreover, forced expression of GAP-43 in PPT1-deficient cells results in 
      the abnormal accumulation of this protein in the ER. Consistent with these 
      results, we found evidence for the activation of unfolded protein response (UPR) 
      marked by elevated levels of phosphorylated translation initiation factor, 
      eIF2alpha, increased expression of chaperone proteins such as glucose-regulated 
      protein-78 and activation of caspase-12, a cysteine proteinase in the ER, 
      mediating caspase-3 activation and apoptosis. Our results, for the first time, 
      link PPT1 deficiency with the activation of UPR, apoptosis and neurodegeneration 
      in INCL and identify potential targets for therapeutic intervention in this 
      uniformly fatal disease.
FAU - Zhang, Zhongjian
AU  - Zhang Z
AD  - Section on Developmental Genetics, Heritable Disorders Branch, National Institute 
      of Child Health and Human Development, 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 - 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  - Intramural NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20051220
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (DNA Primers)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (GAP-43 Protein)
RN  - 0 (Molecular Chaperones)
RN  - 10028-17-8 (Tritium)
RN  - EC 3.1.2.- (Thiolester Hydrolases)
RN  - EC 3.1.2.22 (palmitoyl-protein thioesterase)
SB  - IM
MH  - Animals
MH  - Apoptosis/*genetics
MH  - Blotting, Western
MH  - Brain/metabolism/ultrastructure
MH  - Cells, Cultured
MH  - DNA Primers
MH  - Endoplasmic Reticulum/genetics/metabolism/pathology
MH  - Eukaryotic Initiation Factor-2/metabolism
MH  - GAP-43 Protein/metabolism
MH  - Immunoprecipitation
MH  - Mice
MH  - Mice, Knockout
MH  - Microscopy, Electron, Transmission
MH  - Microscopy, Fluorescence
MH  - Molecular Chaperones/metabolism
MH  - Neuronal Ceroid-Lipofuscinoses/*genetics/*metabolism
MH  - Neurons/cytology/*pathology
MH  - Thiolester Hydrolases/*deficiency
MH  - Tritium
EDAT- 2005/12/22 09:00
MHDA- 2006/07/13 09:00
CRDT- 2005/12/22 09:00
PHST- 2005/12/22 09:00 [pubmed]
PHST- 2006/07/13 09:00 [medline]
PHST- 2005/12/22 09:00 [entrez]
AID - ddi451 [pii]
AID - 10.1093/hmg/ddi451 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2006 Jan 15;15(2):337-46. doi: 10.1093/hmg/ddi451. Epub 2005 Dec 
      20.