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Lookup NU author(s): Professor Raj Kalaria
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© 2014 American Chemical Society. Dementia is a major public health burden characterized by impaired cognition and loss of function. There are limited treatment options due to inadequate understanding of its pathophysiology and underlying causative mechanisms. Discovery-driven iTRAQ-based quantitative proteomics techniques were applied on frozen brain samples to profile the proteome from vascular dementia (VaD) and age-matched nondementia controls to elucidate the perturbed pathways contributing to pathophysiology of VaD. The iTRAQ quantitative data revealed significant up-regulation of protein-l-isoaspartate O-methyltransferase and sodium-potassium transporting ATPase, while post-translational modification analysis suggested deamidation of catalytic and regulatory subunits of sodium-potassium transporting ATPase. Spontaneous protein deamidation of labile asparagines, generating abnormal l-isoaspartyl residues, is associated with cell aging and dementia due to Alzheimers disease and may be a cause of neurodegeneration. As ion channel proteins play important roles in cellular signaling processes, alterations in their function by deamidation may lead to perturbations in membrane excitability and neuronal function. Structural modeling of sodium-potassium transporting ATPase revealed the close proximity of these deamidated residues to the catalytic site during E2P confirmation. The deamidated residues may disrupt electrostatic interaction during E1 phosphorylation, which may affect ion transport and signal transduction. Our findings suggest impaired regulation and compromised activity of ion channel proteins contribute to the pathophysiology of VaD.
Author(s): Adav SS, Qian J, Ang YL, Kalaria RN, Lai MKP, Chen CP, Sze SK
Publication type: Article
Publication status: Published
Journal: Journal of Proteome Research
Print publication date: 07/11/2014
Online publication date: 25/08/2014
Acceptance date: 13/02/2014
ISSN (print): 1535-3893
ISSN (electronic): 1535-3907
Publisher: American Chemical Society
PubMed id: 25152327
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