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首页> 外文期刊>Neuropathology: official journal of the Japanese Society of Neuropathology >Reduced brain-derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF-immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum
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Reduced brain-derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF-immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum

机译：脊髓小脑性共济失调6型（SCA6）小脑的脑源性神经营养因子（BDNF）mRNA表达降低和BDNF免疫反应性颗粒的存在

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Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder caused by a small expansion of tri-nucleotide (CAG) repeat encoding polyglutamine (polyQ) in the gene for α1A voltage-dependent calcium channel (Cav2.1). Thus, this disease is one of the nine neurodegenerative disorders called polyQ diseases. The Purkinje cell predominant neuronal loss is the characteristic neuropathology of SCA6, and a 75-kDa carboxy-terminal fragment (CTF) of Cav2.1 containing polyQ, which remains soluble in normal brains, becomes insoluble in the cytoplasm of SCA6 Purkinje cells. Because the suppression of the brain-derived neurotrophic factor (BDNF) expression is a potentially momentous phenomenon in many other polyQ diseases, we implemented BDNF expression analysis in SCA6 human cerebellum using quantitative RT-PCR for the BDNF mRNA, and by immunohistochemistry for the BDNF protein. We observed significantly reduced BDNF mRNA levels in SCA6 cerebellum (n=3) compared to controls (n=6) (Mann-Whitney U-test, P=0.0201). On immunohistochemistry, BDNF protein was only weakly stained in control cerebellum. On the other hand, we found numerous BDNF-immunoreactive granules in dendrites of SCA6 Purkinje cells. We did not observe similar BDNF-immunoreactive granules in other polyQ diseases, such as Huntington's disease or SCA2. As we often observed that the 1C2-positive Cav2.1 aggregates existed more proximally than the BDNF-positive granules in the dendrites, we speculated that the BDNF protein trafficking in dendrites may be disturbed by Cav2.1 aggregates in SCA6 Purkinje cells. We conclude that the SCA6 pathogenic mechanism associates with the BDNF mRNA expression reduction and abnormal localization of BDNF protein.
机译：脊髓小脑性共济失调6型（SCA6）是常染色体显性遗传性神经退行性疾病，由α1A电压依赖性钙通道（Cav2.1）基因中编码聚谷氨酰胺（polyQ）的三核苷酸（CAG）重复序列的小扩增引起。因此，该疾病是九种称为polyQ疾病的神经退行性疾病之一。浦肯野细胞主要的神经元丢失是SCA6的特征性神经病理学，而含polyQ的Cav2.1的75 kDa羧基末端片段（CTF）仍可溶于正常大脑，变得不溶于SCA6浦肯野细胞的细胞质。因为在许多其他polyQ疾病中抑制脑源性神经营养因子（BDNF）表达是潜在的重大现象，所以我们在SCA6人小脑中使用定量RT-PCR对BDNF mRNA进行了BDNF表达分析，并对BDNF进行了免疫组织化学分析蛋白。我们观察到与对照组（n = 6）相比，SCA6小脑（n = 3）的BDNF mRNA水平显着降低（Mann-Whitney U检验，P = 0.0201）。在免疫组化中，BDNF蛋白仅在对照小脑中被弱染色。另一方面，我们在SCA6 Purkinje细胞的树突中发现了许多BDNF免疫反应性颗粒。我们在其他polyQ疾病（如亨廷顿氏病或SCA2）中未观察到类似的BDNF免疫反应性颗粒。由于我们经常观察到1C2阳性Cav2.1聚集体比树突中的BDNF阳性颗粒更近端存在，我们推测SCA6浦肯野细胞中的Cav2.1聚集体可能会干扰BDNF在树突中的蛋白运输。我们得出结论，SCA6的致病机制与BDNF mRNA表达降低和BDNF蛋白异常定位有关。

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