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Decreased transcription factor junD in brains of patients with Down syndrome
O Labudova1, K Krapfenbauer, H Moenkemann
1Department of Pediatrics, University of Vienna, Austria.
Abstract:
JunD is a member of the Jun family of transcription factors (TF), recently shown to negatively regulate cell growth and antagonizes transformation by the protooncogene ras: c-jun decreases while junD is accumulating when fibroblasts become quiescent. Furthermore, overexpression of junD resulted in slower growth and an increase in cells in G0/G1. 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 with 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 controls, whereas junD levels were significantly and remarkably reduced in frontal, temporal lobe and cerebellum of patients with DS. These findings 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 downregulated junD at the mRNA level revealed by the gene hunting technique (subtractive hybridization) in fetal DS brain. We propose that junD plays a role for the impaired development and wiring of DS brain, maybe already early in life.
Insights
JunD protein levels are significantly reduced in the brains of individuals with Down syndrome (DS), suggesting a role in impaired brain development. This finding is specific to DS and not linked to Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- JunD, a transcription factor, negatively regulates cell growth and antagonizes oncogene-induced transformation.
- Overexpression of JunD leads to slower cell growth and increased cells in the G0/G1 phase.
- A sequence homologous to JunD was found downregulated in fetal Down syndrome (DS) brain.
Purpose of the Study:
- To investigate JunD protein levels in adult brain specimens from individuals with DS, Alzheimer's disease (AD), and controls.
- To determine if reduced JunD levels in DS are associated with AD-like neuropathology.
Main Methods:
- Western blot analysis was performed on five brain regions from aged patients with DS (n=9), controls (n=9), and AD (n=9).
- Gene hunting techniques (subtractive hybridization) were used to assess JunD mRNA levels in fetal DS brain.
Main Results:
- JunD protein levels in AD brains were comparable to controls.
- JunD levels were significantly reduced in the frontal lobe, temporal lobe, and cerebellum of patients with DS.
- Downregulated JunD mRNA was also observed in fetal DS brain.
Conclusions:
- Reduced JunD levels represent a specific finding in DS brains.
- The observed reduction in JunD is not linked to AD-like neuropathological changes (plaques and tangles).
- JunD may play a role in the impaired development and neural wiring of the DS brain, potentially from early life stages.