Polyubiquitinylation profile in down syndrome brain before and after the development of Alzheimer neuropathology

Antonella Tramutola, Fabio Di Domenico, Eugenio Barone, Andrea Arena, Alessandra Giorgi, Laura Di Francesco, Maria Eugenia Schininà, Raffaella Coccia, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Aims: 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. Results: 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. Innovation: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)280-298
Number of pages19
JournalAntioxidants and Redox Signaling
Volume26
Issue number7
DOIs
StatePublished - Mar 1 2017

Bibliographical note

Publisher Copyright:
© Mary Ann Liebert, Inc.

Keywords

  • Alzheimer disease
  • Down syndrome
  • Proteasome
  • Proteomics
  • Trisomy21
  • Ubiquitin

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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