Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice
Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice
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DOI：
10.1523/jneurosci.0857-08.2008
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发表时间：
2008-06-11
影响因子：
5.3
通讯作者：
Yang, X. William
中科院分区：
文献类型：
--
作者：
Gray, Michelle;Shirasaki, Dyna I.;Yang, X. William
为了阐明全长人突变型亨廷顿蛋白（fl-mhtt）表达诱导的亨廷顿病（HD）的致病机制，建立了细菌人工染色体（BAC）介导的转基因小鼠模型（BACHD），该转基因小鼠在BAC上的内源性htt调节机制的控制下表达具有97个谷氨酰胺重复序列的fl-mhtt。BACHD小鼠表现出进行性运动缺陷、神经元突触功能障碍和迟发性选择性神经病理学，其包括显著的皮质和纹状体萎缩和纹状体暗神经元变性。功效分析揭示了行为和神经病理表型的稳健性，表明BACHD是用于临床前研究的合适的fl-mhtt小鼠模型。对BACHD小鼠的其他分析为mhtt如何引起神经发病机制提供了新的见解。首先，与先前的fl-mhtt小鼠模型不同，BACHD小鼠揭示了HD小鼠脑中的缓慢进行性和选择性致病过程可以在没有聚集的mhtt的早期和弥漫性核积累的情况下发生（即，如用EM 48抗体免疫染色所检测的）。相反，相对稳态水平的主要全长mhtt和少量的mhtt N-末端片段足以引发疾病过程。第二，BACHD小鼠中fl-mhtt内的多聚谷氨酰胺重复序列由混合CAA-CAG重复序列编码，其在神经病理学发作时在种系和体细胞组织（包括皮质和纹状体）中均稳定。因此，我们的研究结果表明，体细胞重复序列不稳定性并没有发挥必要的作用，在BACHD小鼠的选择性神经发病机制。总之，BACHD模型构成了研究HD发病机制和治疗的新型且强大的体内范式。
To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.