Department of Psychiatry and Biobehavioral Sciences, Center for Neurobehavioral Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Neuron. 2011 May 12;70(3):427-40. doi: 10.1016/j.neuron.2011.03.021.
Huntington's disease-like-2 (HDL2) is a phenocopy of Huntington's disease caused by CTG/CAG repeat expansion at the Junctophilin-3 (JPH3) locus. The mechanisms underlying HDL2 pathogenesis remain unclear. Here we developed a BAC transgenic mouse model of HDL2 (BAC-HDL2) that exhibits progressive motor deficits, selective neurodegenerative pathology, and ubiquitin-positive nuclear inclusions (NIs). Molecular analyses reveal a promoter at the transgene locus driving the expression of a CAG repeat transcript (HDL2-CAG) from the strand antisense to JPH3, which encodes an expanded polyglutamine (polyQ) protein. Importantly, BAC-HDL2 mice, but not control BAC mice, accumulate polyQ-containing NIs in a pattern strikingly similar to those in the patients. Furthermore, BAC mice with genetic silencing of the expanded CUG transcript still express HDL2-CAG transcript and manifest polyQ pathogenesis. Finally, studies of HDL2 mice and patients revealed CBP sequestration into NIs and evidence for interference of CBP-mediated transcriptional activation. These results suggest overlapping polyQ-mediated pathogenic mechanisms in HD and HDL2.
亨廷顿病样 2 型（HDL2）是由 Junctophilin-3（JPH3）基因位点的 CTG/CAG 重复扩展引起的亨廷顿病的表型副本。HDL2 发病机制的机制仍不清楚。在这里，我们开发了一种 BAC 转基因 HDL2 小鼠模型（BAC-HDL2），该模型表现出进行性运动缺陷、选择性神经退行性病变和泛素阳性核内包涵体（NI）。分子分析显示，转基因位点的启动子驱动了与 JPH3 链反义的 CAG 重复转录本（HDL2-CAG）的表达，该转录本编码扩展的多聚谷氨酰胺（polyQ）蛋白。重要的是，BAC-HDL2 小鼠而非对照 BAC 小鼠在与患者非常相似的模式中积累了含有 polyQ 的 NI。此外，具有扩增 CUG 转录物遗传沉默的 BAC 小鼠仍表达 HDL2-CAG 转录物并表现出 polyQ 发病机制。最后，对 HDL2 小鼠和患者的研究揭示了 CBP 被隔离到 NI 中，并且证据表明 CBP 介导的转录激活受到干扰。这些结果表明在 HD 和 HDL2 中存在重叠的 polyQ 介导的致病机制。
