Poster Sessions

CI -3

Arjun Saha

A. Saha, S. Kim, Z. Zhang, Y. Lee, C. Sarkat, P. Tsai, A. B. Mukherjee

S100B-RAGE signaling mediates neuroinflammation in INCL

Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, cumulatively represent the most common (1 in 12,500 births) neurodegenerative storage disorders of childhood. The infantile NCL (INCL) is the most devastating disease caused by palmitoyl-protein thioesterase 1 (PPT1) deficiency. We previously reported that in INCL, endoplasmic reticulum (ER)- and oxidative-stresses mediate neuronal apoptosis. Because the ER is the major organelle for Ca++ storage, ER-stress disrupts Ca++ homeostasis releasing Ca++ into the cytosol. Using post mortem brain tissues from an INCL patient and those of the PPT1-KO mice, we report here that the PPT1-deficient brain tissues express high levels of S100B, a Ca++-binding protein, and its receptor, RAGE (receptor for advanced glycation end-product). We also demonstrate that RAGE-signaling activates Src- as well as MAP-kinases and stimulates the activation of the transcription factor, NF-B, which mediates the production of pro-inflammatory cytokines. Blocking of RAGE expression by SiRNA mediated gene silencing down-regulates activation of Src, MAP kinases and as well as production of proinflammatory cytokines in PPT1-KO cells. These results for the first time links PPT1-deficiency to ER-Stress mediated activation of the S100B-RAGE signaling pathway leading to neuroinflammation in INCL and identifies S100B-RAGE pathway as a potential therapeutic target for this devastating disease