title: Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: clues for understanding the development of Alzheimer disease.
abstract: Down syndrome (DS) is the most common genetic cause of intellectual disability, due to partial or complete triplication of chromosome 21. DS subjects are characterized by a number of abnormalities including premature aging and development of Alzheimer disease (AD) neuropathology after approximately 40 years of age. Several studies show that oxidative stress plays a crucial role in the development of neurodegeneration in the DS population. Increased lipid peroxidation is one of the main events causing redox imbalance within cells through the formation of toxic aldehydes that easily react with DNA, lipids, and proteins. In this study we used a redox proteomics approach to identify specific targets of 4-hydroxynonenal modifications in the frontal cortex from DS cases with and without AD pathology. We suggest that a group of identified proteins followed a specific pattern of oxidation in DS vs young controls, probably indicating characteristic features of the DS phenotype; a second group of identified proteins showed increased oxidation in DS/AD vs DS, thus possibly playing a role in the development of AD. The third group of comparison, DS/AD vs old controls, identified proteins that may be considered specific markers of AD pathology. All the identified proteins are involved in important biological functions including intracellular quality control systems, cytoskeleton network, energy metabolism, and antioxidant response. Our results demonstrate that oxidative damage is an early event in DS, as well as dysfunctions of protein-degradation systems and cellular protective pathways, suggesting that DS subjects are more vulnerable to oxidative damage accumulation that might contribute to AD development. Further, considering that the majority of proteins have been already demonstrated to be oxidized in AD brain, our results strongly support similarities with AD in DS.
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Gilda
authors.initials: G
authors.lastname: Pupo
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tramutola
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giorgi
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Schininà
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Coccia
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA; Department of Chemistry and Center of Membrane Sciences, University of Kentucky, Lexington, KY 40506-0055, USA.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy. Electronic address: Marzia.perluigi@uniroma1.it.
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
mesh_terms: D000293:Adolescent; D000328:Adult; D000447:Aldehydes / Q000378:metabolism*; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002648:Child; D018450:Disease Progression; D004314:Down Syndrome / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D040901:Proteomics
chemical_list: D000447:Aldehydes; D009419:Nerve Tissue Proteins; C027576:4-hydroxy-2-nonenal
keywords: Alzheimer disease; Down syndrome; Free radicals; HNE; Lipid peroxidation; Protein oxidation; Redox proteomics; Trisomy 21