Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer's disease neuropathology: Redox proteomics analysis of human brain

Fabio Di Domenico, Raffaella Coccia, Annalisa Cocciolo, M. Paul Murphy, Giovanna Cenini, Elizabeth Head, D. Allan Butterfield, Alessandra Giorgi, Maria Eugenia Schinina, Cesare Mancuso, Chiara Cini, Marzia Perluigi

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105 Scopus citations


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 40. years 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.

Original languageEnglish
Pages (from-to)1249-1259
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number8
StatePublished - Aug 2013

Bibliographical note

Funding Information:
This work is partially supported by PRIN2009 to C.C. and C.M. and NIH [ AG-05119 ] to D.A.B. Brain tissue was acquired by EH under funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging Grant #NIH 1RO1HD064993-01 .

Funding Information:
DS and young control cases (8 for each group) were obtained from the University of California-Irvine Alzheimer's Disease Research Center Brain Tissue Repository (supported by NIH NIA Grant #P50 AG16573.), the Eunice Kennedy Shriver NICHD Brain and Tissue Bank for Developmental Disorders (University of Maryland, Baltimore, MD, contract HHSN275200900011C, Ref. No. N01-HD-9-0011). Table 1 shows the characteristics and demographic data of the subjects included in the study. The mean post mortem interval (PMI) is 12.1 ± 4.7 h for CTR subjects and 13.3 ± 2.1 h for DS subjects.


  • Alzheimer disease
  • Autophagy
  • Down syndrome
  • Oxidative stress
  • Proteasome
  • Trisomy 21

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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