Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration

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

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Abstract

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 A2 (cPLA2) 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 cPLA2-catalyzed LPC production in the brain is at least one of the mechanisms that mediate phagocyte infiltration contributing to INCL neuropathology.

Original languageEnglish
Pages (from-to)837-847
Number of pages11
JournalHuman Molecular Genetics
Volume16
Issue number7
DOIs
StatePublished - Apr 2007

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Cytosolic Phospholipases A2
Lysophosphatidylcholines
Phagocytes
Neuronal Ceroid-Lipofuscinoses
Brain
Caspase 12
Ceroid
Apoptosis
Unfolded Protein Response
Neurons
Protein Deficiency
Endoplasmic Reticulum Stress
Brain Death
Microglia
Lysosomes
palmitoyl-protein thioesterase
Cadaver
Knockout Mice
Astrocytes
Neurodegenerative Diseases

ASJC Scopus subject areas

  • Genetics

Cite this

Zhang, Z., Lee, Y. C., Kim, S. J., Choi, M. S., Tsai, P. C., Saha, A., ... Mukherjee, A. B. (2007). Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration. Human Molecular Genetics, 16(7), 837-847. https://doi.org/10.1093/hmg/ddm029

Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration. / Zhang, Zhongjian; Lee, Yi Ching; Kim, Sung Jo; Choi, Moonsuk S.; Tsai, Pei Chih; Saha, Arjun; Wei, Hui; Xu, Yan; Xiao, Yi Jin; Zhang, Peng; Heffer, Alison; Mukherjee, Anil B.

In: Human Molecular Genetics, Vol. 16, No. 7, 04.2007, p. 837-847.

Research output: Contribution to journalArticle

Zhang, Z, Lee, YC, Kim, SJ, Choi, MS, Tsai, PC, Saha, A, Wei, H, Xu, Y, Xiao, YJ, Zhang, P, Heffer, A & Mukherjee, AB 2007, 'Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration', Human Molecular Genetics, vol. 16, no. 7, pp. 837-847. https://doi.org/10.1093/hmg/ddm029
Zhang, Zhongjian ; Lee, Yi Ching ; Kim, Sung Jo ; Choi, Moonsuk S. ; Tsai, Pei Chih ; Saha, Arjun ; Wei, Hui ; Xu, Yan ; Xiao, Yi Jin ; Zhang, Peng ; Heffer, Alison ; Mukherjee, Anil B. / Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration. In: Human Molecular Genetics. 2007 ; Vol. 16, No. 7. pp. 837-847.
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abstract = "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 A2 (cPLA2) 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 cPLA2-catalyzed LPC production in the brain is at least one of the mechanisms that mediate phagocyte infiltration contributing to INCL neuropathology.",
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AU - Tsai, Pei Chih

AU - Saha, Arjun

AU - Wei, Hui

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AU - Heffer, Alison

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