Disulfide bridge formation prevents CaMKII/Calmodulin interaction in Parkinson's disease
Di Maio, R.; General, I. J.; Furbee, E.; Ayoobc, J. C.; Castro, S. L.; Bahar, I.; Greenamyre, J. T.; Pullara, F.
Show abstract
There is increasing evidence for disordered Ca2+ signaling in dopamine neurons in Parkinsons 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 vitro and in vivo investigations 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.
Matching journals
The top 11 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Glycated alpha-synuclein assemblies cause distinct Parkinsons disease pathogenesis in mice 93%
- A subtle structural modification of a synthetic cannabinoid receptor agonist drastically increases its efficacy at the CB1 receptor 92%
- Sigma receptor ligands are potent anti-prion compounds that act independently of sigma receptor binding 92%
Similar papers in this journal
- Queuine, a bacterial derived hypermodified nucleobase, shows protection in in vitro models of neurodegeneration 94%
- Age-dependent neuroprotective effect of an SK3. channel agonist on excitotoxityto dopaminergic neurons in organotypic culture 93%
- Transport of Alzheimer's Associated Amyloid-β Catalyzed by P-glycoprotein 93%
Similar papers in this journal
- Live cell imaging of single neurotrophin receptor molecules on human neuron in Alzheimer's disease 94%
- Small-molecule inhibitors of the RNA m6A demethylase FTO potently support the survival of dopamine neurons 93%
- Transcriptional and Histone acetylation changes associated with CRE elements expose key factors governing the regulatory circuit in early stage of Huntington's disease models. 93%
Similar papers in this journal
- JNK signalling regulates antioxidant responses in neurons 94%
- Redox signaling by hydrogen peroxide modulates axonal microtubule organization and induces a specific phosphorylation signature of microtubule proteins distinct from distress 93%
- An increase in surface hydrophobicity mediates chaperone activity in N-chlorinated proteins 93%
Similar papers in this journal
- Long-term dynamic changes of NMDA receptors following an excitotoxic challenge 93%
- Functional characterization of Neurofilament Light b splicing and misbalance in zebrafish 93%
- Heparan sulfates regulate axonal excitability and context generalization through Ca2+/calmodulin-dependent protein kinase II 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.