科研之友
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摘要
X-chromosomal dystonia parkinsonism syndrome (XDP, olubag%26apos;) is associated with sequence changes within the TAF1/DYT3 multiple transcript system. Although most sequence changes are intronic, one, disease-specific single-nucleotide change 3 (DSC3), is located within an exon (d4). Transcribed exon d4 occurs as part of multiple splice variants. These variants include exons d3 and d4 spliced to exons of TAF1, and an independent transcript composed of exons d2d4. Location of DSC3 in exon d4 and utilization of this exon in multiple splice variants suggest an important role of DSC3 in the XDP pathogenesis. To test this hypothesis, we transfected neuroblastoma cells with four expression constructs, including exons d2d4 [d2d4/wild-type (wt) and d2-d4/DSC3] and d3d4 (d3d4/wt and d3d4/DSC3). Expression profiling revealed a dramatic effect of DSC3 on overall gene expression. Three hundred and sixty-two genes differed between cells containing d2d4/wt and d2d4/DSC3. Annotation clustering revealed enrichment of genes related to vesicular transport, dopamine metabolism, synapse function, Ca-2 metabolism and oxidative stress. Two hundred and eleven genes were differentially expressed in d3d4/wt versus d3d4/DSC3. Annotation clustering highlighted genes in signal transduction and cellcell interaction. The data show an important role of physiologically occurring transcript d2d4 in normal brain function. Interference with this role by DSC3 is a likely pathological mechanism in XDP. Disturbance of dopamine function and of Ca-2 metabolism can explain abnormal movement; loss of protection against reactive oxygen species may account for the neurodegenerative changes in XDP. Although d3d4 also affect genes potentially related to neurodegenerative processes, their physiologic role as splice variants of TAF1 awaits further exploration.
- 出版日期2013-3-1
