NADPH oxidase 2 activity disrupts Calmodulin/CaMKIIα complex via redox modifications of CaMKIIα-contained Cys30 and Cys289: Implications in Parkinson's disease

Ca 2 + /calmodulin-dependent protein kinase II alpha (CaMKII alpha) signaling in the brain plays a critical role in regulating neuronal Ca 2 + homeostasis. Its dysfunctional activity is associated with various neurological and neurodegenerative disorders, including Parkinson's disease (PD). Using computational modeling analysis, we predicted that, two essential cysteine residues contained in CaMKII alpha, Cys30 and Cys289, may undergo redox modifications impacting the proper functioning of the CaMKII alpha docking site for Ca 2 + /CaM, thus impeding the formation of the CaMKII alpha:Ca 2 + /CaM complex, essential for a proper modulation of CaMKII alpha kinase activity. Our subsequent in vitro investigations confirmed the computational predictions, specifically implicating Cys30 and Cys289 residues in impairing CaMKII alpha:Ca 2 + /CaM interaction. We observed CaMKII alpha:Ca 2 + /CaM complex disruption in dopamine (DA) nigrostriatal neurons of post-mortem Parkinson's disease (PD) patients' specimens, addressing the high relevance of this event in the disease. CaMKII alpha:Ca 2 + /CaM complex disruption was also observed in both in vitro and in vivo rotenone models of PD, where this phenomenon was associated with CaMKII alpha kinase hyperactivity. Moreover, we observed that, NADPH oxidase 2 (NOX2), a major enzymatic generator of superoxide anion (O (center dot-)(2) ) and hydrogen peroxide (H 2 O 2 ) in the brain with implications in PD pathogenesis, is responsible for CaMKII alpha:Ca 2 + /CaM complex disruption associated to a stable Ca 2 + CAM-independent CaMKII alpha kinase activity and intracellular Ca 2 + accumulation. The present study highlights the importance of oxidative stress, in disturbing the delicate balance of CaMKII alpha signaling in calcium dysregulation, offering novel insights into PD pathogenesis.