Murage Brenda, Tan Han, Mashimo Tomoji, Jackson Mandy, Skehel Paul A
Centre for Discovery Brain Sciences, Edinburgh University, Edinburgh EH8 9XD, UK.
Euan MacDonald Centre for MND Research, Edinburgh University, Edinburgh EH16 4SB, UK.
Brain Commun. 2024 May 24;6(3):fcae184. doi: 10.1093/braincomms/fcae184. eCollection 2024.
Amyotrophic lateral sclerosis is an age-dependent cell type-selective degenerative disease. Genetic studies indicate that amyotrophic lateral sclerosis is part of a spectrum of disorders, ranging from spinal muscular atrophy to frontotemporal dementia that share common pathological mechanisms. Amyotrophic lateral sclerosis Type 8 is a familial disease caused by mis-sense mutations in . VAPB is localized to the cytoplasmic surface of the endoplasmic reticulum, where it serves as a docking point for cytoplasmic proteins and mediates inter-organelle interactions with the endoplasmic reticulum membrane. A gene knock-in model of amyotrophic lateral sclerosis Type 8 based on the mutation and gene deletion has been generated in rats. These animals display a range of age-dependent phenotypes distinct from those previously reported in mouse models of amyotrophic lateral sclerosis Type 8. A loss of motor neurones in and animals is indicated by a reduction in the number of large choline acetyl transferase-staining cells in the spinal cord. animals exhibit a relative increase in cytoplasmic TDP-43 levels compared with the nucleus, but no large protein aggregates. Concomitant with these spinal cord pathologies , and animals exhibit age-dependent changes in paw placement and exerted pressures when traversing a CatWalk apparatus, consistent with a somatosensory dysfunction. Extramotor dysfunction is reported in half the cases of motor neurone disease, and this is the first indication of an associated sensory dysfunction in a rodent model of amyotrophic lateral sclerosis. Different rodent models may offer complementary experimental platforms with which to understand the human disease.
肌萎缩侧索硬化症是一种与年龄相关的细胞类型选择性退行性疾病。遗传学研究表明，肌萎缩侧索硬化症是一系列疾病的一部分，范围从脊髓性肌萎缩症到额颞叶痴呆症，它们具有共同的病理机制。8型肌萎缩侧索硬化症是一种由……中的错义突变引起的家族性疾病。VAPB定位于内质网的细胞质表面，在那里它作为细胞质蛋白的停靠点，并介导与内质网膜的细胞器间相互作用。基于……突变和……基因缺失构建了大鼠8型肌萎缩侧索硬化症基因敲入模型。这些动物表现出一系列与先前报道的8型肌萎缩侧索硬化症小鼠模型不同的年龄依赖性表型。脊髓中大型胆碱乙酰转移酶染色细胞数量减少表明……和……动物的运动神经元丧失。与细胞核相比，……动物的细胞质TDP - 43水平相对增加，但没有大的蛋白质聚集体。与这些脊髓病变同时发生的是，……和……动物在通过CatWalk装置时，爪放置和施加压力出现年龄依赖性变化，这与体感功能障碍一致。在运动神经元疾病病例中，有一半报告存在运动外功能障碍，这是8型肌萎缩侧索硬化症啮齿动物模型中相关感觉功能障碍的首个迹象。不同的啮齿动物模型可能提供互补的实验平台，用于了解人类疾病。
