Selective upregulation of the ubiquitin-proteasome proteolytic pathway proteins, proteasome zeta chain and isopeptidase T in fetal Down syndrome

The ubiquitin-proteasome proteolytic pathway is involved in an important no n-lysosomal proteolytic pathway that is responsible for the highly selectiv e turnover of cellular proteins both under basal metabolic conditions as we ll as stress. Protein degradation by this pathway is attributed to the 20S proteasome that forms the catalytic core of the complex. Recently there has been increasing interest in the proteasome because of its possible role in neuron degeneration and death. Fetal Down syndrome (DS) neurons were demon strated to degenerate and undergo apoptosis in vitro. We therefore investig ated the expression of different proteins involved in this degradative path way, including subunits of the 20S proteasome, ubiquitinating and deubiquit inating enzymes, and regulatory subunits of the 26S proteasome in control a nd DS fetal brains by two-dimensional electrophoresis (2-DE). After 2-DE, a pproximately 389 protein spots were successfully identified by matrix-assoc iated laser desorption ionization mass spectroscopy (MALDI-MS) and this was followed by quantification of twenty three proteins of the pathway. The re sults indicate that all but two proteins exhibited no apparent alterations in their pattern of expression. Proteasome zeta chain, an alpha subunit of the 20S proteasome (P < 0.05) and ubiquitin carboxy-terminal hydrolase T (I sopeptidase T), a deubiquitinating enzyme (P < 0.001) were significantly in creased in fetal DS compared to controls. Whilst the expression of proteaso me iota (n = 9. r = -0.9489, P = 0.0004) and proteasome epsilon (n = 9, r = -0.7227, P = 0.0311) chains was decreased with age in fetal DS brain, no s ignificant correlation was obtained in the other proteins with age. The dat a suggest that such selective upregulation may have relevance to the develo pmental abnormalities that characterize this disorder.