MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.
Neuroscience. 2010 May 19;167(3):774-85. doi: 10.1016/j.neuroscience.2010.02.035. Epub 2010 Feb 24.
Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.
在运动神经元内含有 TAR-DNA 结合蛋白-43（TDP-43）的细胞质泛素阳性包涵物是散发性肌萎缩侧索硬化症（ALS）的标志性病理学特征。TDP-43 是一种核蛋白，其在 ALS 中发生错误定位和聚集的机制尚未得到充分理解。囊泡相关膜蛋白相关蛋白-B（VAPB）中的突变涉及脯氨酸到丝氨酸的 56 位取代（VAPBP56S），是家族性 ALS 型 8 的原因。为了深入了解 VAPBP56S 诱导疾病的分子机制，我们创建了在神经系统中表达野生型 VAPB（VAPBwt）或 VAPBP56S 的转基因小鼠。对这两组小鼠的分析均未发现明显的运动表型或生存改变。然而，只有 VAPBP56S 而非 VAPBwt 转基因小鼠在脊髓运动神经元中出现细胞质 TDP-43 积累，该积累在 18 个月时首次被检测到。我们的结果表明异常 VAPBP56S 功能与 TDP-43 错误定位之间存在联系。
