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.
|Number of pages||19|
|Journal||Antioxidants and Redox Signaling|
|State||Published - Mar 1 2017|
Bibliographical noteFunding Information:
Brain tissue was acquired by E.H. under funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging (Grant No. NIH 1RO1HD064993-01). Autopsy tissue was obtained from the UCI-ADRC (P50AG16573), from the UK ADC (P30AG28383), and from the NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland (Baltimore, MD) contract HHSN275200900011C (N01HD90011).
© Mary Ann Liebert, Inc.
- Alzheimer disease
- Down syndrome
ASJC Scopus subject areas
- Molecular Biology
- Clinical Biochemistry
- Cell Biology