RAGE signaling contributes to neuroinflammation in infantile neuronal ceroid lipofuscinosis |
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Authors: | Saha Arjun Kim Sung-Jo Zhang Zhongjian Lee Yi-Ching Sarkar Chinmoy Tsai Pei-Chih Mukherjee Anil B |
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Affiliation: | Section on Developmental Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, United States |
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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 Ca2+-homeostasis and stimulates the expression of Ca2+-binding proteins. We report here that in the PPT1-deficient human and mouse brain the levels of S100B, a Ca2+-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. |
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Keywords: | INCL, infantile neuronal ceroid lipofuscinosis PPT1, palmitoyl-protein thioesterase-1 RAGE, receptor for advanced glycation end products ER, endoplasmic reticulum CNS, central nervous system GROD, granular osmiophilic deposit |
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