The University of Sydney, Brain and Mind Centre and Central Clinical School, Faculty of Medicine and Health, Camperdown, NSW 2006, Australia.
Neuroscience Research Australia, Randwick, NSW 2031, Australia.
Brain. 2020 Mar 1;143(3):783-799. doi: 10.1093/brain/awaa039.
Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
额颞叶痴呆和肌萎缩性侧索硬化症在临床上和病理学上有重叠，具有共同的遗传原因。我们之前在一个具有常染色体显性遗传的额颞叶痴呆和肌萎缩性侧索硬化症的大型欧洲澳大利亚家族中，在染色体 16p12.1-q12.2 上发现了一个具有全基因组显著连锁的疾病位点，并且在已知的肌萎缩性侧索硬化症或痴呆症基因中没有突变。在这里，我们证明了在这个家族中，连锁区域内 CYLD（c.2155A>G，p.M719V）的一种新型错义变体的分离是疾病的遗传原因。对两个 CYLD p.M719V 突变携带者脑组织的免疫组织化学分析显示广泛的神经胶质 CYLD 免疫反应性。用 CYLDM719V 转染的原代小鼠神经元表现出 TDP-43 的细胞质定位增加和轴突缩短。CYLD 编码一种赖氨酸 63 去泛素化酶，CYLD 皮肤综合征是一种皮肤肿瘤疾病，由导致去泛素化酶活性降低的突变引起。与 CYLD 皮肤综合征致病突变相反，CYLDM719V 相对于野生型酶表现出显著增加的赖氨酸 63 去泛素化酶活性（配对 Wilcoxon 符号秩检验 P = 0.005）。在 HEK293 细胞中过度表达 CYLDM719V 导致细胞信号分子 NF-κB 的更有效抑制和自噬体与溶酶体融合的损伤，这是自噬的关键过程。尽管 CYLD 突变似乎很少见，但 CYLD 与至少另外三种由额颞叶痴呆症和/或肌萎缩性侧索硬化症基因（TBK1、OPTN 和 SQSTM1）编码的蛋白质相互作用表明，它可能在这些疾病的发病机制中发挥核心作用。包括 TBK1、OPTN 和 SQSTM1 在内的几个额颞叶痴呆症和肌萎缩性侧索硬化症基因的突变导致自噬功能丧失。我们在这里表明，增加的 CYLD 活性也降低了自噬功能，突出了自噬调节在额颞叶痴呆症和肌萎缩性侧索硬化症发病机制中的重要性。
