Molecular mechanism of the carboxyl terminus of Hsc70-interacting protein in TAU hyperphosphorylation induced by AlCl3 in N2a cells

Abstract

Aluminum (Al) is recognized as a neurotoxin. Studies have confirmed that the neurotoxicity induced by Al may be related to tau hyperphosphorylation. Phosphorylated tau is degraded through the ubiquitin-proteasome pathway (UPP), in which the carboxyl terminus of Hsc70-interacting protein (CHIP) plays an important role. However, whether the CHIP plays a role in regulating tau hyperphosphorylation induced by Al is yet to be determined. The purpose of this study was to explore the molecular mechanism of the CHIP in tau hyperphosphorylation induced by AlCl3 in N2a cells. Mouse neuroblastoma cells (N2a) were exposed to different concentrations of AlCl3 (0, 0.5, 1, and 2 mM) and treated with CHIP/CHIP shRNA/CHIP (ΔU-box)/CHIP (ΔTPR) plasmid transfection. The cell viability was determined by the CCK-8 kit. Protein expression was detected by Western blot. The interaction between CHIP and AlCl3 exposure on the proteins was analyzed by factorial design ANOVA. The results showed that Al can cause tau hyperphosphorylation, mainly affecting the pThr231, pSer262, and pSer396 sites of tau in N2a cells. UPP is involved in the degradation of tau hyperphosphorylation induced by Al in N2a cells, of which CHIP may be the main regulatory target. Both the U-box and TPR domains of CHIP are indispensable and play an important role in the regulation of tau hyperphosphorylation induced by AlCl3 in N2a cells.