The Role of Glia in Canine Degenerative Myelopathy: Relevance to Human Amyotrophic Lateral Sclerosis
The Role of Glia in Canine Degenerative Myelopathy: Relevance to Human Amyotrophic Lateral Sclerosis
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DOI：
10.1007/s12035-019-1488-3
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发表时间：
2019-08-01
影响因子：
5.1
通讯作者：
Walczak, Piotr
中科院分区：
文献类型：
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作者：
Golubczyk, Dominika;Malysz-Cymborska, Izabela;Walczak, Piotr
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以运动神经元进行性变性为特征的致死性神经退行性疾病。在过去的十年中，对神经退行性疾病的研究指出了胶质细胞在支持神经元正常功能中的作用。特别是，少突胶质细胞被证明是必不可少的，通过髓鞘的生产和供应轴突与能量代谢物通过单羧酸转运蛋白（MCT）。我们使用了患有自然发生的退行性脊髓病（DM）的犬，其与在人类ALS中观察到的特征非常相似。我们对脊髓组织样本进行了两种类型的分析：组织学分析和分子分析。组织学包括从在不同疾病阶段死于DM的狗中收集的样本，将其与年龄匹配的对照组进行比较，并将其置于年轻脊髓的背景下。对患有晚期DM的脊髓和年龄匹配的样本进行分子分析，包括与神经元、少突胶质细胞、髓鞘和MCT功能相关的选定基因产物的实时PCR分析。在患有DM的狗中，通过色素染色的损失和与髓鞘相关的基因（包括MBP、Olig1和Olig2）的表达降低检测到脱髓鞘。MCT1和MCT2的显著减少以及MCT4表达的增加表明神经元的能量供应受到干扰。虽然Rbfox3的表达没有改变，但ChAT的产生受到负面影响。狗中的DM再现了人ALS的主要特征，包括运动神经元的丧失、神经元能量供应的失调和髓磷脂的丧失，因此是ALS治疗方法的高度转化研究的理想模型系统。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons and grim prognosis. Over the last decade, studies on neurodegenerative diseases pointed on the role of glia in supporting the proper function of neurons. Particularly, oligodendrocytes were shown to be essential through myelin production and supplying axons with energy metabolites via monocarboxylate transporters (MCT). We have used dogs with naturally occurring degenerative myelopathy (DM) which closely resembles features observed in human ALS. We have performed two types of analysis of spinal cord tissue samples: histology and molecular analysis. Histology included samples collected from dogs that succumbed to the DM at different disease stages, which were compared to age-matched controls as well as put in the context of young spinal cords. Molecular analysis was performed on spinal cords with advanced DM and age-matched samples and included real-time PCR analysis of selected gene products related to the function of neurons, oligodendrocytes, myelin, and MCT. Demyelination has been detected in dogs with DM through loss of eriochrome staining and decreased expression of genes related to myelin including MBP, Olig1, and Olig2. The prominent reduction of MCT1 and MCT2 and increased MCT4 expression is indicative of disturbed energy supply to neurons. While Rbfox3 expression was not altered, the ChAT production was negatively affected. DM in dogs reproduces main features of human ALS including loss of motor neurons, dysregulation of energy supply to neurons, and loss of myelin, and as such is an ideal model system for highly translational studies on therapeutic approaches for ALS.