Elevated expression of S100B and RAGE positively correlates with pro‐inflammatory cytokine production that may contributie to rapid neurodegeneration in INCL

Abstract

Infantile neuronal ceroid lipofuscinosis (INCL) is caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 cleaves thioester linkages in S-acylated (palmitoylated) proteins and its mutation causes abnormal accumulation of fatty-acylated polypeptides leading to INCL pathogenesis. We recently reported that neuronal apoptosis in INCL is at least in part caused by endoplasmic reticulum (ER) stress activating unfolded protein response (UPR) and caspase activation. It has been reported that ER stress disrupts Ca2+ homeostasis and stimulates the production of reactive oxygen species (ROS). Here, we report that the levels of Ca2+ binding protein, S100B, in human INCL as well as in the PPT1-KO mice that mimic INCL, are markedly elevated. We also demonstrate that the expression of a receptor for S-100B, RAGE (advanced glycation end products), is also significantly increased. We further demonstrate that elevated levels of S-100B and RAGE expression is positively correlated with increased level of Src-phosphorylation and IL-6 as well as MCP-1 gene expression in cultured neurospheres from PPT1-KO mice. We propose that: PPT1-deficiency-mediated ER stress increases ROS production and disrupts calcium homeostasis, which in turn stimulates S100B over-expression and S-100B interaction with RAGE activates signaling pathway(s) stimulating pro-inflammatory mediator production and apoptosis contributing to rapid neurodegeneration in INCL.