Pathological cell-cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice
Pathological cell-cell interactions elicited by a neuropathogenic form of mutant huntingtin contribute to cortical pathogenesis in HD mice
复制标题
DOI：
10.1016/j.neuron.2005.03.025
复制
发表时间：
2005-05-05
期刊：
影响因子：
16.2
通讯作者：
Yang, XW
中科院分区：
文献类型：
--
作者：
Gu, XF;Li, CJ;Yang, XW
已知亨廷顿舞蹈病（HID）以及其他多q疾病中的扩增多谷氨酰胺（polyQ）蛋白可引起多种细胞内毒性，但尚不清楚多q蛋白是否可引起病理性细胞-细胞相互作用，这对疾病发病机制至关重要。为了测试这种可能性，我们在离散的神经元群体中创造了条件性HD小鼠，表达一种神经致瘤形式的突变亨廷顿蛋白（mhttexon1）。我们发现mhtt聚集是一个细胞自主的过程。然而，进行性运动障碍和皮质神经病变仅在mhtt表达于多种神经元类型时才会出现，包括皮质间神经元，而mhtt表达仅限于皮质锥体神经元时则不会出现。我们进一步证明了皮层抑制的早期缺陷，表明中间神经元和锥体神经元之间的病理相互作用可能有助于HD的皮层表现。我们的研究提供了遗传学证据，证明由神经源性mhtt形式引发的病理性细胞-细胞相互作用可能对HD小鼠模型的皮层发病机制起关键作用。
Expanded polyglutamine (polyQ) proteins in Huntington's disease (HID) as well as other polyQ disorders are known to elicit a variety of intracellular toxicities, but it remains unclear whether polyQ proteins can elicit pathological cell-cell interactions which are critical to disease pathogenesis. To test this possibility, we have created conditional HD mice expressing a neuroplathogenic form of mutant huntingtin (mhtt-exon1) in discrete neuronal populations. We show that mhtt aggregation is a cell-autonomous process. However, progressive motor deficits and cortical neuropathology are only observed when mhtt expression is in multiple neuronal types, including cortical inter-neurons, but not when mhtt expression is restricted to cortical pyramidal neurons. We further demonstrate an early deficit in cortical inhibition, suggesting that pathological interactions between interneurons and pyramidal neurons may contribute to the cortical manifestation of HD. Our study provides genetic evidence that pathological cell-cell interactions elicited by neuroplathogenic forms of mhtt can critically contribute to cortical pathogenesis in a HD mouse model.