Ser423-phosphorylated MECP2 (MECP2-pS423) Accumulates in Human Brain, Cerebrospinal Fluid, and Serum in Sporadic Alzheimer’s Disease
Kevin Perez1, Qing-Rong Liu2, Josephine Egan3
1Neurology, Rutgers NJMS, 2National Institute on Aging, National Institutes of Health, National Institute on Aging US, 3Laboratory of Clinical Investigation, National Institute of Aging
Objective:
To determine whether neuron activity dependent phosphorylation of human methyl-CpG-binding protein 2 (MECP2) at serine 423 (MECP2-pS423) plays a role in Alzheimer’s disease (AD) and to evaluate its potential as a biomarker and therapeutic agent.
Background:
MECP2 is a DNA methyl-CpG binding protein that functions as a global epigenetic repressor. Activity dependent phosphorylation of mouse Mecp2 at Ser421 facilitates its translocation from nucleus to the cytoplasm, diminishing its repressor function and activating neurotrophins. In AD mouse models (APP/PS1), increased Mecp2-pS421 levels in neuronal soma and activation of glycogen synthase kinase-3 beta (GSK3B) suggest a connection between Mecp2 phosphorylation and Tau pathology. However, the significance of the corresponding phosphorylation site in human MECP2 (Ser423) remains unknown.
Design/Methods:
Our team developed a MECP2-pS423 specific antibody and a quantitative selective reaction monitoring assay using liquid chromatography tandem mass spectrometry. Immunohistochemistry and proteomic analyses were performed on human postmortem temporal cortex, hippocampus, cerebrospinal fluid and serum. Expression patterns were correlated with clinicopathological stage and cognitive measures.
Results:
MECP2-pS423 expression increased progressively across the clinicopathological spectrum of AD in brain tissue which also correlated with histological severity and cognitive decline. MECP2-pS423 colocalized with phosphorylated Tau (pTau) in granulovacuolar degeneration bodies (GVD) and neuritic plaques. Elevated MECP2-pS423 phosphoprotein levels were also detected in CSF and serum of AD patients.
Conclusions:
Phosphorylation of MECP2 at Ser423 is (MECP2-pS423) is closely associated with AD pathology and cognitive impairment. Its accumulation in brain, CSF, and serum highlights MECP2-pS423 as a potential mechanism-based biomarker and therapeutic target for human sporadic Alzheimer’s Disease.
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