期刊
JOURNAL OF PROTEOME RESEARCH
卷 13, 期 11, 页码 4635-4646出版社
AMER CHEMICAL SOC
DOI: 10.1021/pr500754j
关键词
dementia; Na plus /K plus -ATPase; ion channel proteins; iTRAQ; mass spectrometry
资金
- U.K. Medical Research Council (MRC) [G0400074]
- Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Diseases
- Alzheimer's Society
- Alzheimer's Research U.K. (ARUK) as part of the Brains for Dementia Research Project
- Singapore National Research Foundation under CBRG [NMRC/CBRG/0004/2012]
- CSA [NMRC/CSA/032/2011]
- Newcastle Centre for Brain Ageing and Vitality, U.K. MRC [G0500247]
- Alzheimer's Research U.K.
- Medical Research Council [G1100540, G0900652, G0500247, G0400074, G0502157] Funding Source: researchfish
- MRC [G1100540, G0500247, G0400074, G0502157, G0900652] Funding Source: UKRI
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 Alzheimer's 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.
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