Office for People With Developmental Disabilities

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Molecular Neurobiology Laboratory

07/12/12

Narayan Ramakrishna, PhD, Acting Head

[email protected]

The objectives of the Molecular Neurobiology Laboratory are to identify significant changes in gene regulation leading to the pathology of Down syndrome (DS) due to triplication of part of chromosome 21. We are studying the role of non–chromosome 21 gene expression changes in the manifestation of pathological phenotype(s). We have studied gene regulation changes in the Ts65Dn mouse model of DS. A simple PCR-based genotyping protocol to identify trisomic mice was developed earlier in this laboratory.

Highlights of the laboratory’s efforts include the following:

Epigenetic regulation of SNCA expression in DS: We have discovered that alpha-synuclein (SNCA), a synaptic protein involved in synaptic transmission, is down-regulated in several regions of Ts65Dn. We hypothesize that decreased mental functions in DS are a result of reduced SNCA functions. To understand the mechanism of regulation of SNCA expression, we performed bisulfite-sequencing analyses of promoter proximal region (intron1). The results indicate that Ts65Dn has significantly reduced methylation level compared to controls. EGCG, a polyphenolic catechin present in green tea, restores the SNCA expression and promoter methylation level in Ts65Dn mice. This finding suggests that methylation of the promoter proximal region of SNCA plays a critical role in the regulation of its expression. Current research is focused on identifying the target of EGCG treatment in Ts65Dn brain.

Regulation of synaptophysin in Ts65Dn mice: We have examined synaptophysin (syp) regulation to determine whether other synaptic proteins share similar regulation as alpha synuclein in Ts65Dn mice. Syp is a pre-synaptic protein involved in synaptic transmission, which is necessary for learning, cognition, and memory processes. Syp expression is not significantly altered in Ts65Dn compared to control brain, unlike alpha synuclein expression. Syp expression increases with age in control and Ts65Dn mice. Syp expression and promoter methylation remain unaltered by EGCG administration, unlike SNCA promoter methylation and expression. Analyses of synaptosomal preparation from Ts65Dn brain indicate that all major components of synaptic vesicles are altered, suggesting a possible causal role in synaptic deficiency leading to mental retardation in DS victims. Current research is aimed at testing the validity of this hypothesis.