Suppression of aggregate formation of mutant huntingtin potentiates CREB-binding protein sequestration and apoptotic cell death

Although aggregates of mutant huntingtin are a pathological hallmark of Huntington's disease (HD), the role of inclusions in the pathogenesis remains inconclusive. Sequestration of CBP into mutant huntingtin has been reported to play a significant role in the pathogenesis of HD. However, whether aggregate formation of mutant huntingtin is necessary for the sequestration of CBP is not fully elucidated. In the present study, YFP was linked into either N- or C-terminus of exon 1 huntingtin to modulate the aggregation propensity of huntingtin. Efficient aggregation was observed with C-terminally YFP-tagged huntingtin (MT-YFP) whereas N-terminally YFP-tagged mutant huntingtin (YFP-MT) exhibited significantly attenuated aggregation frequency. The sequestration of CBP and apoptosis were significantly increased with YFP-MT. Microarray study showed transcriptional changes favoring apoptosis. Furthermore, expression of PGC1-α was significantly decreased with YFP-MT. The data strongly demonstrate that microscopically non-aggregate form of mutant huntingtin might exert essential pathogenic role of mutant huntingtin in HD.