RAGE signaling contributes to neuroinflammation in infantile neuronal ceroid lipofuscinosis

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.

Abbreviations: 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

Keywords: Neuroinflammation, Neurodegeneration, Infantile neuronal ceroid lipofuscinosis, Batten disease, Palmitoyl-protein thioesterase-1