Signaling Mechanisms and Disrupted Cytoskeleton in the Diphenyl Ditelluride Neurotoxicity
Figure 6
Effects of the in vivo treatment with (PhTe)2 on neural cells of young rats. (a) Schematic representation of the proposed mechanism of (PhTe)2-induced disruption of the IF-associated phosphorylating system in brain of young rats in vivo. (PhTe)2 activates cell surface receptors eliciting signaling cascades through intracellular second messengers, which activate the cyclic AMP- and Ca2+/calmodulin-dependent protein kinases (PKA and PKCaMII, resp.). Also, MAP kinases (Erk1/2; JNK, and p38MAPK) are activated, targeting specific sites on IF subunits. PKA and PKCaMII phosphorylate serine sites, such as Ser55 on NF-L, and MAPKs are directed to KSP repeats on the C-terminal domain on NF-M and NF-H. The hyperphosphorylated N-terminal domain misregulates the association/disassociation equilibrium of the filaments, while C-terminal hyperphosphorylation disrupts the interaction of the filaments with other cytoskeletal elements and with motor proteins. In box, chemical structure of phosphorylated amino acids. (b) The cerebellar damage induced by the in vivo exposure to (PhTe)2. Increased GFAP staining, one of the main features of reactive astrogliosis, is concomitant with decreased NeuN positive cells, indicative of reduced neuronal cells. Adapted from Heimfarth et al., 2013 [64].
