Author:
Di Maio Roberto,General Ignacio J.,Furbee Emily,Ayoob Joseph C.,Castro Sandra L.,Bahar Ivet,Greenamyre J. Timothy,Pullara Filippo
Abstract
AbstractThere is increasing evidence for disordered Ca2+signaling in dopamine neurons in Parkinson’s disease (PD), and this likely involves altered Ca2+/calmodulin-dependent protein kinase II (CaMKII) function. Previous work suggests that oxidative stress - a major feature in PD pathogenesis - affects regulatory methionine residues that sustain CaMKII activity in a Ca2+/CaM-independent manner. Here, applying computational modeling, we predicted formation of a defined disulfide bridge close to the CaMKII docking site for Ca2+/CaM binding.In vitroandin vivoinvestigations using PD models revealed formation of a disulfide bridge and loss of the CaMKII–calmodulin interaction. Mutagenesis of the relevant cysteine residues abrogated disulfide bridge formation and recovered the CaMKII–calmodulin interaction. Importantly, dopamine neurons from post-mortem PD brain specimens also lost this regulatory protein-protein interaction, providing relevance in the human disease. This study provides novel insights into oxidative CaMKII-CaM dysfunction, which may contribute to the pathophysiology of PD.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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1. Calmodulin and Its Binding Proteins in Parkinson’s Disease;International Journal of Molecular Sciences;2021-03-16