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Human Molecular Genetics Advance Access published online on December 20, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi451
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Published by Oxford University Press 2005
Received October 11, 2005
Revised December 8, 2005
Accepted December 8, 2005

Article

Palmitoyl-Protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL

Zhongjian Zhang 1, Yi-Ching Lee 1, Sung-Jo Kim 1, Moonsuk S. Choi 1, Pei-Chih Tsai 1, Yan Xu 2, Yi-Jin Xiao 2, Peng Zhang 3, Alison Soltys 1, and Anil B. Mukherjee 1 *

1 Section on Developmental Genetics, Heritable Disorders Branch, National Institute of Child Health and Human development, The National Institutes of Health, Bethesda, Maryland 20892-1830
2 Department of Cancer Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195
3 Walter Reed Army Institute of Research, Silver Spring, Maryland, MD 20910-7500

* To whom correspondence should be addressed.
Anil B. Mukherjee, E-mail: mukherja{at}exchange.nih.gov


  Abstract

Numerous proteins undergo modification by palmitic acid (s-acylation) for their biological functions including signal transduction, vesicular transport and maintenance of cellular architecture. While palmitoylation is an essential modification, these proteins must also undergo de-palmitoylaton 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 causes infantile neuronal ceroid lipofuscinoses (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, are elevated in the brains of PPT1-KO mice. Moreover, forced expression of GAP-43 in PPT1-deficient cells results in 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, eIF2{alpha}, increased expression of chaperone proteins such as glucose-regulated protein-78 (Grp-78/Bip) 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.


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