Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice.
Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice.
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DOI：
10.1093/hmg/11.6.633
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发表时间：
2002-03
影响因子：
3.5
通讯作者：
V. Wheeler;C. Gutekunst;V. Vrbanac;Lori-Anne Lebel;Gabriele Schilling;S. Hersch;R. Friedlander;J. Gusella;J. Vonsattel;D. Borchelt;M. MacDonald
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作者：
V. Wheeler;C. Gutekunst;V. Vrbanac;Lori-Anne Lebel;Gabriele Schilling;S. Hersch;R. Friedlander;J. Gusella;J. Vonsattel;D. Borchelt;M. MacDonald
在亨廷顿病（HD）中，CAG重复序列延长了亨廷顿蛋白中的谷氨酰胺通道，引发纹状体神经元的显性丢失和舞蹈病。神经病理学变化包括形成不溶性突变N-末端片段，如核/神经细胞包涵体和过滤陷阱淀粉样蛋白，其可能参与疾病过程或为降解副产物。在年轻的Hdh基因敲入小鼠中，CAG将小鼠亨廷顿蛋白中的谷氨酰胺束扩展至儿童期发病HD长度，导致全长突变亨廷顿蛋白的核积累和随后不溶性片段的积累。在这里，我们报告迟发性神经退行性变和步态缺陷的老年Hdh（Q111）基因敲入小鼠，表明核表型包括早期阶段的疾病过程中，符合遗传和病理标准确定的HD患者。此外，使用早期的核积累表型作为替代标记，我们在遗传实验中表明，疾病的过程中，启动全长突变蛋白，是加速突变片段的共表达，因此，在已经受损的神经元不溶性产物的积累可能会加剧发病机制。相反，正常亨廷顿蛋白或突变型半胱天冬酶-1并没有改变早期疾病事件的发生时间，这两种蛋白质在其他HD模型中显示出减少夹杂物和谷氨酰胺毒性。因此，人类的潜在HD治疗可能针对不同的水平：预防疾病引发机制或减缓随后的发病机制进展。
In Huntington's disease (HD), CAG repeats extend a glutamine tract in huntingtin to initiate the dominant loss of striatal neurons and chorea. Neuropathological changes include the formation of insoluble mutant N-terminal fragment, as nuclear/neuropil inclusions and filter-trap amyloid, which may either participate in the disease process or be a degradative by-product. In young Hdh knock-in mice, CAGs that expand the glutamine tract in mouse huntingtin to childhood-onset HD lengths lead to nuclear accumulation of full-length mutant huntingtin and later accumulation of insoluble fragment. Here we report late-onset neurodegeneration and gait deficits in older Hdh(Q111) knock-in mice, demonstrating that the nuclear phenotypes comprise early stages in a disease process that conforms to genetic and pathologic criteria determined in HD patients. Furthermore, using the early nuclear-accumulation phenotypes as surrogate markers, we show in genetic experiments that the disease process, initiated by full-length mutant protein, is hastened by co-expression of mutant fragment; therefore, accrual of insoluble-product in already compromised neurons may exacerbate pathogenesis. In contrast, timing of early disease events was not altered by normal huntingtin or by mutant caspase-1, two proteins shown to reduce inclusions and glutamine toxicity in other HD models. Thus, potential HD therapies in man might be directed at different levels: preventing the disease-initiating mechanism or slowing the subsequent progression of pathogenesis.