title: Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer's disease neuropathology: redox proteomics analysis of human brain.
abstract: DS is the most frequent genetic cause of intellectual disability characterized by the anomalous presence of three copies of chromosome 21. One of the peculiar features of DS is the onset of Alzheimer's disease neuropathology after the age of 40years characterized by deposition of senile plaques and neurofibrillary tangles. Growing studies demonstrated that increased oxidative damage, accumulation of unfolded/damaged protein aggregates and dysfunction of intracellular degradative system are key players in neurodegenerative processes. In this study, redox proteomics approach was used to analyze the frontal cortex from DS subjects under the age of 40 compared with age-matched controls, and proteins found to be increasingly carbonylated were identified. Interestingly, our results showed that oxidative damage targets specifically different components of the intracellular quality control system such as GRP78, UCH-L1, V0-ATPase, cathepsin D and GFAP that couples with decreased activity of the proteasome and autophagosome formation observed. We also reported a slight but consistent increase of Aβ 1-42 SDS- and PBS-soluble form and tau phosphorylation in DS versus CTR. We suggest that disturbance in the proteostasis network could contribute to the accumulation of protein aggregates, such as amyloid deposits and NFTs, which occur very early in DS. It is likely that a sub-optimal functioning of degradative systems occur in DS neurons, which in turn provide the basis for further accumulation of toxic protein aggregates. The results of this study suggest that oxidation of protein members of the proteostatis network is an early event in DS and might contribute to neurodegenerative phenomena.
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.forename: Raffaella
authors.initials: R
authors.lastname: Coccia
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cocciolo
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenini
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giorgi
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Schinina
authors.forename: Cesare
authors.initials: C
authors.lastname: Mancuso
authors.forename: Chiara
authors.initials: C
authors.lastname: Cini
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
mesh_terms: D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016022:Case-Control Studies; D002402:Cathepsin D / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D010588:Phagosomes / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D050050:Protein Carbonylation / Q000502:physiology; D040901:Proteomics / Q000379:methods; D057165:Proteostasis Deficiencies / Q000378:metabolism* / Q000473:pathology; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D055815:Young Adult; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C482860:UCHL1 protein, human; D016875:tau Proteins; D043222:Ubiquitin Thiolesterase; C533922:CTSD protein, human; D002402:Cathepsin D; D046988:Proteasome Endopeptidase Complex