title: Aberrant protein phosphorylation in Alzheimer disease brain disturbs pro-survival and cell death pathways.
abstract: Protein phosphorylation of serine, threonine, and tyrosine residues is one of the most prevalent post-translational modifications fundamental in mediating diverse cellular functions in living cells. Aberrant protein phosphorylation is currently recognized as a critical step in the pathogenesis and progression of Alzheimer disease (AD). Changes in the pattern of protein phosphorylation of different brain regions are suggested to promote AD transition from a presymptomatic to a symptomatic state in response to accumulating amyloid β-peptide (Aβ). Several experimental approaches have been utilized to profile alteration of protein phosphorylation in the brain, including proteomics. Among central pathways regulated by kinases/phosphatases those involved in the activation/inhibition of both pro survival and cell death pathways play a central role in AD pathology. We discuss in detail how aberrant phosphorylation could contribute to dysregulate p53 activity and insulin-mediated signaling. Taken together these results highlight that targeted therapeutic intervention, which can restore phosphorylation homeostasis, either acting on kinases and phosphatases, conceivably may prove to be beneficial to prevent or slow the development and progression of AD.
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Perluigi
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy; Universidad Autónoma de Chile, Instituto de Ciencias Biomédicas, Facultad de Salud, Providencia, Santiago, Chile.
authors.forename: E
authors.initials: E
authors.lastname: Barone
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Di Domenico
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA. Electronic address: dabcns@uky.edu.
authors.forename: D A
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D002470:Cell Survival; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D007328:Insulin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: Alzheimer disease; Insulin; Protein phosphorylation; Proteomics; p53