Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.
Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
J Neurol Neurosurg Psychiatry. 2020 Feb;91(2):162-171. doi: 10.1136/jnnp-2019-321790. Epub 2019 Nov 5.
Since the first report of gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia.
Whole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation in . CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology.
No causal, novel or disease-associated variants in were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease.
Genetic variation in is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.
自肌萎缩侧索硬化症（ALS）/额颞叶痴呆（FTD）患者首次报道 基因突变以来， 基因的遗传变异与疾病的相关性一直不一致。患者神经元组织中 CHCHD10 蛋白的病理评估也有待报道。我们试图描述 CHCHD10 对澳大利亚 ALS/FTD 的遗传和病理贡献。
对 81 例家族性和 635 例散发性 ALS 以及 108 例散发性 FTD 患者的全外显子组和全基因组测序数据进行评估，以确定 基因中的遗传变异。通过免疫组织化学、免疫荧光和 Western blot 分析，在对照、ALS 和/或 FTD 尸检组织中进一步在 TAR DNA 结合蛋白 43（TDP-43）病理的转基因小鼠模型中对 CHCHD10 蛋白表达进行了特征描述。
在澳大利亚 ALS 和/或 FTD 患者中未发现 中的因果、新的或疾病相关变异。在人脑和脊髓组织中，CHCHD10 特异性表达于神经元中。在 ALS 患者的脊髓和 FTD 患者的额皮质中观察到 CHCHD10 蛋白水平显著降低。在具有可调节核定位信号（rNLS TDP-43 小鼠）的 TDP-43 小鼠模型中，CHCHD10 蛋白水平在疾病发作和早期疾病时没有改变，但在疾病中期皮质中显著降低。
基因中的遗传变异不是澳大利亚 ALS/FTD 的常见原因。然而，我们表明，在人类中，CHCHD10 可能发挥神经元特异性作用，并且 CHCHD10 功能的丧失可能与 ALS 和/或 FTD 相关。我们来自 rNLS TDP-43 转基因小鼠的数据表明，CHCHD10 水平的降低是异常 TDP-43 诱导的 ALS/FTD 发病机制中的晚期事件。
