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Human Molecular Genetics Advance Access originally published online on December 20, 2005
Human Molecular Genetics 2006 15(2):337-346; doi:10.1093/hmg/ddi451
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Published by Oxford University Press 2005

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

Zhongjian Zhang1, Yi-Ching Lee1, Sung-Jo Kim1, Moonsuk S. Choi1, Pei-Chih Tsai1, Yan Xu2, Yi-Jin Xiao2, Peng Zhang3, Alison Heffer1 and Anil B. Mukherjee1,*

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

* To whom correspondence should be addressed. Tel: +1 3014967213; Fax: +1 3014026632; Email: mukherja{at}exchange.nih.gov

Received October 11, 2005; Accepted December 8, 2005

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, eIF2{alpha}, 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.


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