title: Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology.
abstract: Among the putative mechanisms proposed to be common factors in Down syndrome (DS) and Alzheimer's disease (AD) neuropathology, deficits in protein quality control (PQC) have emerged as a unifying mechanism of neurodegeneration. Considering that disturbance of protein degradation systems is present in DS and that oxidized/misfolded proteins require polyubiquitinylation for degradation via the ubiquitin proteasome system, this study investigated if dysregulation of protein polyubiquitinylation is associated with AD neurodegeneration in DS.
  
  
  
  Postmortem brains from DS cases before and after development of AD neuropathology and age-matched controls were analyzed. By selectively isolating polyubiquitinated proteins, we were able to identify specific proteins with an altered pattern of polyubiquitinylation as a function of age. Interestingly, we found that oxidation is coupled with polyubiquitinylation for most proteins mainly involved in PQC and energy metabolism.
  
  
  
  This is the first study showing alteration of the polyubiquitinylation profile as a function of aging in DS brain compared with healthy controls. Understanding the onset of the altered ubiquitome profile in DS brain may contribute to identification of key molecular regulators of age-associated cognitive decline.
  
  
  
  Disturbance of the polyubiquitinylation machinery may be a key feature of aging and neurodegeneration. In DS, age-associated deficits of the proteolytic system may further exacerbate the accumulation of oxidized/misfolded/polyubiquitinated proteins, which is not efficiently degraded and may become harmful to neurons and contribute to AD neuropathology. Antioxid. Redox Signal. 26, 280-298.
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tramutola
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Domenico
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Barone
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Andrea
authors.initials: A
authors.lastname: Arena
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giorgi
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Laura
authors.initials: L
authors.lastname: di Francesco
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Schininà
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Coccia
authors.affiliation: 2 Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky.|3 Department of Pharmacology and Nutritional Sciences, University of Kentucky , Lexington, Kentucky.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.affiliation: 2 Sanders-Brown Center on Aging, University of Kentucky , Lexington, Kentucky.|4 Department of Chemistry, University of Kentucky , Lexington, Kentucky.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: 1 Department of Biochemical Sciences, Sapienza University of Rome , Italy, Rome.
authors.forename: Marzia
authors.initials: M
authors.lastname: Perluigi
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004314:Down Syndrome / Q000150:complications* / Q000378:metabolism*; D006801:Humans; D025821:Polyubiquitin / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D025821:Polyubiquitin; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex
keywords: Alzheimer disease; Down syndrome; proteasome; proteomics; trisomy21; ubiquitin