Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability
Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability
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DOI：
10.1007/s00401-019-01976-3
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发表时间：
2019-06-01
影响因子：
12.7
通讯作者：
De Klippel, Nina
中科院分区：
文献类型：
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作者：
Cacace, Rita;Heeman, Bavo;De Klippel, Nina
新的证据表明，神经退行性脑疾病（NBD）中存在一种聚合机制，涉及早期神经元网络功能障碍和神经元放电稳态的改变，这是神经退行性变的罪魁祸首。在这项研究中，我们使用配对末端短读长和直接长读长全基因组测序来研究与 7q36 显着相关的未解决的常染色体显性痴呆家族。我们鉴定并验证了 ca 的染色体倒位。 4Mb，分离疾病单倍型并破坏二肽基肽酶 6 基因 (DPP6) 的编码序列。 DPP6 重测序在早发性阿尔茨海默病（EOAD，p 值 = 0.03，OR = 2.21 95% CI 1.05-4.82）和额颞叶痴呆（FTD，p = 0.006，OR = 2.59，95% CI 1.28-5.49）患者中发现了明显更罕见的变异——无义、移码和错义。队列。 DPP6 是一种 II 型跨膜蛋白，具有高度结构化的细胞外结构域，主要在大脑中表达，与钾通道 K(v)4.2 结合增强其表达，调节其门控特性并控制海马神经元的树突状兴奋性。通过体外模型，我们发现患者体内发现的错义变异会破坏 DPP6 的稳定性并降低其膜表达（p < 0.001 和 p < 0.0001），从而导致蛋白质损失。在错义变异携带者的脑组织中也检测到 DPP6 和/或 K(v)4.2 表达减少。已知 DPP6 缺失会导致 Dpp6-KO 小鼠神经元过度兴奋和行为改变。总而言之，我们的基因组、遗传、表达和建模分析的结果提供了支持 DPP6 缺失与痴呆有关的直接证据。我们认为，功能缺失变异具有更高的外显率和疾病影响，而错义变异对疾病的风险贡献不同，外显率从高到低不等。我们对 DPP6 作为痴呆症新基因的发现，强化了神经元过度兴奋和神经元放电稳态改变的参与，作为一种疾病机制，有待进一步研究。
Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frame-shift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K(v)4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K(v)4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.