DECREASED TRANSCRIPTION FACTOR JUND IN BRAINS OF PATIENTS WITH DOWN-SYNDROME

JunD is a member of the Jun family of transcription factors (TF), rece ntly shown to negatively regulate cell growth and antagonizes transfor mation by the protooncogene ras: c-jun decreases while junD is accumul ating when fibroblasts become quiescent. Furthermore, overexpression o f junD resulted in slower growth and an increase in cells in G(0)/G(1) . Performing gene hunting on fetal Down syndrome (DS) brain we found a sequence downregulated and homologous to junD. This observation made us examine junD protein levels in adult brain specimens. Western blot experiments were carried out in five brain regions of aged patients wi th DS (n = 9), controls (n = 9) and patients with Alzheimer's disease (AD, n = 9). We found that junD in AD brains were comparable to contro ls, whereas junD levels were significantly and remarkably reduced in f rontal, temporal lobe and cerebellum of patients with DS. These findin gs may indicate a specific finding in DS and were not linked to the AD -like-neuropathological changes of plaques and tangles, observed in DS from the fourth decade, which is also suggested by the findings of do wnregulated junD at the mRNA level revealed by the gene hunting techni que (subtractive hybridization) in fetal DS brain. We propose that jun D plays a role for the impaired development and wiring of DS brain, ma ybe already early in life. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.