OBJECTIVE Since the first report of CHCHD10 gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in CHCHD10 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. METHODS 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. 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. RESULTS No causal, novel or disease-associated variants in CHCHD10 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. CONCLUSIONS Genetic variation in CHCHD10 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.

中文翻译：

---

遗传和免疫病理分析CHCHD10在澳大利亚的肌萎缩性侧索硬化症和额颞痴呆和转基因TDP-43小鼠中。

目的自首次报道肌萎缩性侧索硬化症（ALS）/额颞叶痴呆（FTD）患者中CHCHD10基因突变以来，CHCHD10的遗传变异与疾病的关系一直不一致。患者神经元组织中CHCHD10蛋白的病理评估也有待报道。我们试图表征CHCHD10对澳大利亚ALS / FTD的遗传和病理学贡献。方法评估了来自81个家族性和635个散发性ALS以及108个散发性FTD病例的全外显子组和全基因组测序数据，以了解CHCHD10的遗传变异。CHCHD10蛋白表达的特征是在对照，ALS和/或FTD死后组织中以及在TAR DNA结合蛋白43（TDP-43）病理学的转基因小鼠模型中通过免疫组织化学，免疫荧光和蛋白质印迹进行表征。结果无因果关系，在澳大利亚的ALS和/或FTD患者中发现了CHCHD10中新的或与疾病相关的变异。在人脑和脊髓组织中，CHCHD10在神经元中特异性表达。在ALS患者的脊髓和FTD患者的额叶皮层中观察到CHCHD10蛋白水平显着降低。在具有可调节核定位信号的TDP-43小鼠模型（rNLS TDP-43小鼠）中，CHCHD10蛋白水平在疾病发作和疾病早期没有改变，但在中期疾病的皮质中显着降低。结论在澳大利亚，CHCHD10的遗传变异不是ALS / FTD的常见原因。但是，我们表明，在人类中，CHCHD10可能起神经元特异性作用，而CHCHD10功能的丧失可能与ALS和/或FTD有关。