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. 2013 Aug;1832(8):1249-59.
doi: 10.1016/j.bbadis.2013.04.013. Epub 2013 Apr 18.

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  1 , 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
Affiliations

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 et al. Biochim Biophys Acta. 2013 Aug.

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.

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Figures

Fig. 1
Fig. 1
Bar graph and WB image of tau phosphorylation (Ser404) and expression levels in CTR and DS samples.
Fig. 2
Fig. 2
Representative 2D gel and blot from DS and CTR samples. The spots showing significantly increased carbonyl levels are labeled. The spot numbers indicated on the maps are the same as those listed in Table 2.
Fig. 3
Fig. 3
Bar graph of identified proteins expression, carbonylation and carbonylation/expression values in CTR and DS samples.
Fig. 4
Fig. 4
Panel A: Bar graph of proteasome subunits (20S and 19S) levels in CTR and DS samples measured by WB analysis. Panel B: Proteasome functionality measured by enzymatic assay of chymotrypsin-like, trypsin-like and caspase-like activity in CTR and DS samples. *p < 0.01.
Fig. 5
Fig. 5
Panel A: Cathepsin D activity in CTR ad DS samples measured by fluorescent assay at 328/393 Ex/Em. Panel B: UCH-L1 activity assay in CTR and DS samples measured by fluorescent assay at 380/460 Ex/Em n = 8; *p < 0.05.
Fig. 6
Fig. 6
LC3 II/I expression levels in CTR and DS samples. Panel A: Bar graph of the ratio of LC3 II and I values compared to β actin loading control. Panel B: Representative bands of LC3 I and II immunodetection in WB analysis. n = 8; *p < 0.05.
Scheme 1
Scheme 1
Putative scenario of QC protein oxidation and Aβ and hpTau degradation/accumulation in DS brain.
See this image and copyright information in PMC

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