文摘
Nitrosative stress mediated S-nitrosylation (SNO) of protein disulfide isomerase (PDI), a housekeeping oxidoreductase, has been implicated in the pathogenesis of sporadic Parkinson鈥檚 (PD) and Alzheimer鈥檚 (AD) diseases. Previous cell line studies have indicated that SNO-PDI formation provokes synphilin-1 aggregation, the minor Parkinsonian biomarker protein. Yet no work exists investigating whether SNO-PDI induces 伪-synuclein aggregation, the major Lewy body constituent associated with Parkinson鈥檚 pathogenesis. Here, we report that SNO-PDI formation is linked to the aggregation of 伪-synuclein and also provokes 伪-synuclein:synphilin-1 deposits (Lewy-body-like debris) normally found in the PD brain. Furthermore, we have examined the ability of a small molecule, 2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione (ellagic acid; EA) to scavenge NOx radicals and to protect cells from SNO-PDI formation via rotenone insult both, cell-based and cell-independent in vitro experiments. Furthermore, EA not only mitigates nitrosative-stress-induced aggregation of synphilin-1 but also 伪-synuclein and 伪-synuclein:synphilin-1 composites (Lewy-like neurites) in PC12 cells. Mechanistic analyses of the neuroprotective phenomena revealed that EA lowered rotenone-instigated reactive oxygen species (ROS) and reactive nitrogen species (RNS) in PC12 cells, imparted antiapoptotic tributes, and directly interfered with SNO-PDI formation. Lastly, we demonstrate that EA can bind human serum albumin (HSA). These results collectively indicate that small molecules can provide a therapeutic foothold for overcoming Parkinson鈥檚 through a prophylactic approach.
Keywords:
Parkinson鈥檚 disease; synphilin-1; 伪-synuclein; ellagic acid; protein disulfide isomerase; rotenone; S-nitrosylation; apoptosis; ER stress; human serum albumin
