Abstract
Palmitoyl-protein thioesterase-1 (PPT1) deficiency causes infantile neuronal ceroid lipofuscinosis (INCL), a devastating childhood neurodegenerative storage disorder. We previously reported that neuronal apoptosis in INCL is mediated by endoplasmic reticulum-stress. ER-stress disrupts Ca(2+)-homeostasis and stimulates the expression of Ca(2+)-binding proteins. We report here that in the PPT1-deficient human and mouse brain the levels of S100B, a Ca(2+)-binding protein, and its receptor, RAGE (receptor for advanced glycation end-products) are elevated. We further demonstrate that activation of RAGE signaling in astroglial cells mediates pro-inflammatory cytokine production, which is inhibited by SiRNA-mediated suppression of RAGE expression. We propose that RAGE signaling contributes to neuroinflammation in INCL.
MeSH terms
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Animals
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Apoptosis
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Astrocytes / metabolism
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Astrocytes / pathology
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Brain / immunology
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Brain / pathology
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Cytokines / biosynthesis
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Encephalitis / genetics
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Encephalitis / immunology*
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Encephalitis / pathology*
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Humans
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase Kinases / metabolism
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NF-kappa B / metabolism
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Nerve Growth Factors / metabolism
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Neuronal Ceroid-Lipofuscinoses / genetics
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Neuronal Ceroid-Lipofuscinoses / immunology*
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Neuronal Ceroid-Lipofuscinoses / pathology*
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RNA, Small Interfering / genetics
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic / agonists
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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S100 Calcium Binding Protein beta Subunit
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S100 Proteins / metabolism
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Signal Transduction
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Thiolester Hydrolases / genetics
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src-Family Kinases / metabolism
Substances
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Cytokines
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NF-kappa B
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Nerve Growth Factors
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RNA, Small Interfering
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic
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S100 Calcium Binding Protein beta Subunit
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S100 Proteins
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S100B protein, human
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S100b protein, mouse
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src-Family Kinases
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Mitogen-Activated Protein Kinase Kinases
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Thiolester Hydrolases
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palmitoyl-protein thioesterase