Synchrotron infrared microspectroscopy detecting the evolution of Huntington's disease neuropathology and suggesting unique correlates of dysfunction in white versus gray brain matter.
Synchrotron infrared microspectroscopy detecting the evolution of Huntington's disease neuropathology and suggesting unique correlates of dysfunction in white versus gray brain matter.
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DOI：
10.1021/ac201102p
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发表时间：
2011-10-15
影响因子：
7.4
通讯作者：
Jeney, Sylvia
中科院分区：
文献类型：
--
作者：
Bonda, Markus;Perrin, Valerie;Vileno, Bertrand;Runne, Heike;Kretlow, Ariane;Forro, Laszlo;Luthi-Carter, Ruth;Miller, Lisa M.;Jeney, Sylvia
亨廷顿病(HD)是由相应的亨廷顿蛋白(HTT)编码基因突变引起的，以认知和运动功能进行性恶化为特征，同时伴有纹状体神经元的广泛丢失。在细胞水平上，发病机制涉及早期和长期的神经元功能障碍，随后是神经元死亡。了解驱动这些有害过程的分子事件对于成功开发减缓或阻止疾病进展的治疗方法至关重要。在这里，我们使用同步加速器辅助傅里叶变换红外光谱仪(S-FTIRM)检测了HD体外大鼠模型以及HD模型中培养神经元的生化过程。该模型基于慢病毒介导的HD基因片段的传递，在一个大脑半球表达突变的HTT片段，在对照半球表达野生型HTT片段。S-傅立叶变换红外光谱仪具有很高的空间分辨率，可以区分灰质和白质中的光谱特征。在突变型HTT暴露后4周，我们在纹状体灰质中检测到较高含量的β-Sheet蛋白。相比之下，白质束没有显示任何蛋白质结构的变化，但令人惊讶的是，不饱和脂肪含量减少，与磷酸化相关的光谱特征显著增加。前者使人联想到与髓鞘形成缺陷相一致的变化，而后者则是早期促凋亡事件的特征。这些发现表明，无标记傅里叶变换红外光谱分析方法可用于跟踪突变型HTT在体外纹状体神经元中的富含β片层的转化，为突变型HTT淀粉样蛋白在体内的发生提供进一步的证据，并展示指示HD白质变化的新的化学特征。在培养的神经元中表达相同HTT片段的平行研究也显示了类似的变化。
Huntington’s disease (HD), caused by a mutation of the corresponding gene encoding the protein huntingtin (htt), is characterized by progressive deterioration of cognitive and motor functions, paralleled by extensive loss of striatal neurons. At the cellular level, pathogenesis involves an early and prolonged period of neuronal dysfunction followed by neuronal death. Understanding the molecular events driving these deleterious processes is critical to the successful development of therapies to slow down or halt the progression of the disease. Here, we examined biochemical processes in a HD ex vivo rat model, as well as in a HD model for cultured neurons using synchrotron-assisted Fourier transform infrared microspectroscopy (S-FTIRM). The model, based on lentiviral-mediated delivery of a fragment of the HD gene, expresses a mutant htt fragment in one brain hemisphere, and a wild-type htt fragment in the control hemisphere. S-FTIRM allowed for high spatial resolution and distinction between spectral features occurring in grey and white matter. We measured a higher content of β-sheet protein in the striatal grey matter exposed to mutant htt as early as 4 weeks following the initiation of mutant htt exposure. In contrast, white matter tracts did not exhibit any changes in protein structure, but surprisingly showed reduced content of unsaturated lipids and a significant increase in spectral features associated with phosphorylation. The former is reminiscent of changes consistent with a myelination deficiency, while the latter is characteristic of early pro-apoptotic events. These findings point to the utility of the label-free FTIRM method to follow mutant htt’s β-sheet-rich transformation in striatal neurons ex vivo, provide further evidence for mutant htt amyloidogenesis in vivo, and demonstrate novel chemical features indicative of white matter changes in HD. Parallel studies in cultured neurons expressing the same htt fragments showed similar changes.
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DOI：
10.1073/pnas.95.11.6118
发表时间：
1998-05-26
影响因子：
11.1
作者：
Georgalis, Y;Starikov, EB;Wanker, EE
通讯作者：
Wanker, EE
影响因子：
5.3
作者：
Díaz-Hernández, M;Moreno-Herrero, F;Lucas, JJ
通讯作者：
Lucas, JJ
影响因子：
2.5
作者：
Miller, LM;Smith, RJ
通讯作者：
Smith, RJ
DOI：
10.1016/j.bbadis.2008.06.004
发表时间：
2008-10-01
影响因子：
6.2
作者：
Kretlow, Ariane;Wang, Qi;Miller, Lisa M.
通讯作者：
Miller, Lisa M.
影响因子：
3.5
作者：
Lewis, EN;Gorbach, AM;Levin, IW
通讯作者：
Levin, IW