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

Zhongjian Zhang, Yi Ching Lee, Sung Jo Kim, Moonsuk S. Choi, Pei Chih Tsai, Yan Xu, Yi Jin Xiao, Peng Zhang, Alison Heffer, Anil B. Mukherjee

Research output: Contribution to journalArticle

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Abstract

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, eIF2α, 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.

Original languageEnglish (US)
Pages (from-to)337-346
Number of pages10
JournalHuman Molecular Genetics
Volume15
Issue number2
DOIs
StatePublished - Jan 15 2006
Externally publishedYes

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Neuronal Ceroid-Lipofuscinoses
Unfolded Protein Response
Apoptosis
Endoplasmic Reticulum
GAP-43 Protein
Proteins
Brain
Caspase 12
Lipoylation
Peptide Initiation Factors
Cysteine Proteases
Acylation
Palmitic Acid
Palmitates
Protein S
Knockout Mice
Caspase 3
Neurodegenerative Diseases
Proteolysis
Atrophy

ASJC Scopus subject areas

  • Genetics

Cite this

Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. / Zhang, Zhongjian; Lee, Yi Ching; Kim, Sung Jo; Choi, Moonsuk S.; Tsai, Pei Chih; Xu, Yan; Xiao, Yi Jin; Zhang, Peng; Heffer, Alison; Mukherjee, Anil B.

In: Human Molecular Genetics, Vol. 15, No. 2, 15.01.2006, p. 337-346.

Research output: Contribution to journalArticle

Zhang, Z, Lee, YC, Kim, SJ, Choi, MS, Tsai, PC, Xu, Y, Xiao, YJ, Zhang, P, Heffer, A & Mukherjee, AB 2006, 'Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL', Human Molecular Genetics, vol. 15, no. 2, pp. 337-346. https://doi.org/10.1093/hmg/ddi451
Zhang, Zhongjian ; Lee, Yi Ching ; Kim, Sung Jo ; Choi, Moonsuk S. ; Tsai, Pei Chih ; Xu, Yan ; Xiao, Yi Jin ; Zhang, Peng ; Heffer, Alison ; Mukherjee, Anil B. / Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in INCL. In: Human Molecular Genetics. 2006 ; Vol. 15, No. 2. pp. 337-346.
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abstract = "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, eIF2α, 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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AU - Zhang, Zhongjian

AU - Lee, Yi Ching

AU - Kim, Sung Jo

AU - Choi, Moonsuk S.

AU - Tsai, Pei Chih

AU - Xu, Yan

AU - Xiao, Yi Jin

AU - Zhang, Peng

AU - Heffer, Alison

AU - Mukherjee, Anil B.

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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, eIF2α, 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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