Two ways to get tangled? Neurodegeneration in Alzheimer's disease dementia is associated with neurofibrillary tangles composed of aggregated tau protein. Darwich et al. describe an additional form of autosomal-dominant dementia with neurofibrillary tangles linked to a hypomorph mutation in valosin-containing protein (VCP). VCP was found to disaggregate pathologic tau, and the hypomorph mutation increased tau accumulation in cells and mice. These findings highlight the role of protein turnover in maintaining neuronal health and suggest that VCP may provide a therapeutic target for Alzheimer's disease. Science, this issue p. eaay8826 An autosomal dominant genetic mutation associated with neurofibrillary degeneration reduces tau disaggregation. INTRODUCTION Alzheimer’s disease (AD) is a fatal neurodegenerative disease in which progressive brain degeneration compromises cognitive function. AD neurodegeneration is tightly associated with abnormal neuronal inclusions called neurofibrillary tangles, which are composed of aggregated tau protein. The importance of tau protein in dementia is highlighted by various known autosomal-dominant mutations in MAPT (microtubule-associated protein tau), the gene that encodes for tau, that are associated with frontotemporal lobar degeneration with tau inclusions (FTLD-tau). Identifying additional disease-causing genes that affect tau accumulation, including genes involved in protein quality control and tau clearance, has the potential to reveal previously unknown mechanisms that maintain neuronal health. RATIONALE Two families were identified with autosomal-dominant dementia linked to a p.Asp395Gly mutation in VCP. Valosin-containing protein (VCP) is a AAA+ [adenosine triphosphatases (ATPases) associated with diverse cellular activities] protein and uses energy from adenosine 5′-triphosphate (ATP) hydrolysis to unfold substrates to assist the dismantling of macromolecular complexes. Other VCP mutations have been identified in a disease called multisystem proteinopathy (MSP), which is associated with neuronal TDP-43 [TAR DNA-binding protein 43] protein inclusions. The mechanisms by which p.Asp395Gly VCP leads to neurodegeneration are unknown. RESULTS Two kindred were identified with an autosomal-dominant inheritance pattern of frontotemporal degeneration linked to a p.Asp395Gly VCP mutation. We have named this disease vacuolar tauopathy because of the presence of neuronal vacuoles and tau aggregates. Tau aggregates were morphologically and biochemically similar to AD neurofibrillary tangles. Moreover, the presence of vacuoles and neurofibrillary tangles in the brain were inversely correlated. Degenerating brain regions such as the frontal neocortex exhibited tau aggregation, whereas nondegenerating brain regions such as the visual cortex exhibited vacuolization. To further characterize the p.Asp395Gly VCP mutation, we assessed recombinant VCP proteins for ATPase activity in an in vitro assay. This approach demonstrated that p.Asp395Gly VCP exhibited a partial loss of ATPase activity, in contrast with MSP mutations, which increase ATPase activity. Given that VCP unfolds protein substrates, we hypothesized that VCP may disaggregate pathologic tau aggregates. Indeed, VCP appeared to partially disaggregate pathologic tau aggregates derived from AD human brain tissues, and the p.Asp395Gly mutation impaired this activity. VCP activity against pathologic tau was energy (ATP) dependent and required polyubiquitination of the tau substrate. In addition, expression of p.Asp395Gly VCP in a cell culture model of tau aggregation was associated with enhanced accumulation of cellular tau aggregates. Last, we generated mice in which the p.Asp395Gly mutation was knocked in, which exhibited a minimal phenotype when unchallenged. However, upon initiating tau aggregation through microinjection of pathologic AD tau extracts into the mouse brain, mutant VCP mice showed an increase in tau accumulation compared with that of wild-type animals. CONCLUSION We describe a partial loss-of-function mutation in VCP that was associated with a neurodegenerative disease, which we named vacuolar tauopathy. VCP appeared to exhibit activity that promoted the disruption of tau aggregates in an energy- and polyubiquitin-dependent manner. Furthermore, the p.Asp395Gly VCP mutation enhanced tau aggregation in a cell culture model system and in a knock-in mouse model. These results highlight a potential role for protein disaggregation in the maintenance of neuronal health. Furthermore, our findings suggest that VCP may provide a potential therapeutic target in the development of future AD therapies. Vacuolar tauopathy and VCP function. Model of tau aggregation, highlighting different mechanisms that lead to neurodegeneration in AD and FTLD-tau. Tau is a soluble protein (green) that forms highly structured fibrils (purple) in AD. Tau aggregates are also a hallmark of FTLD-tau. Autosomal dominant FTLD-tau mutations in MAPT, the gene that encodes tau protein, can alter splicing or enhance tau protein aggregation, which results in the accumulation of insoluble tau inclusions in neurons and glia. VCP (blue) appears to exhibit disaggregase activity against pathologic tau. This activity is dependent on the availability of energy (ATP) and the presence of polyubiquitin on tau protein aggregates. Vacuolar tauopathy is an autosomal-dominant form of dementia linked to a p.Asp395Gly VCP mutation (orange-red). Neurodegeneration in vacuolar tauopathy was associated with tau aggregates of similar biochemical composition and morphology as those seen in Alzheimer’s disease. The accumulation of insoluble tau aggregates in vacuolar tauopathy appeared to be in part due to a partial loss of tau disaggregase function associated with the p.Asp395Gly VCP mutation. WT, wild-type. Neurodegeneration in Alzheimer’s disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly VCP mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.

中文翻译：

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常染色体显性 VCP 亚型突变损害 PHF-tau 的解聚

纠结的两种方式？阿尔茨海默病痴呆症中的神经变性与由聚集的 tau 蛋白组成的神经原纤维缠结有关。达里奇等人。描述了另一种常染色体显性痴呆症，其神经原纤维缠结与含缬乐新蛋白 (VCP) 的亚型突变有关。发现 VCP 可分解病理性 tau，并且亚型突变增加了细胞和小鼠中的 tau 积累。这些发现强调了蛋白质周转在维持神经元健康中的作用，并表明 VCP 可能为阿尔茨海默氏病提供治疗靶点。科学，这个问题 p。eaay8826 与神经原纤维变性相关的常染色体显性遗传突变减少了 tau 分解。简介 阿尔茨海默病 (AD) 是一种致命的神经退行性疾病，其中进行性脑退化会损害认知功能。AD 神经变性与称为神经原纤维缠结的异常神经元包涵体密切相关，神经原纤维缠结由聚集的 tau 蛋白组成。tau 蛋白在痴呆症中的重要性通过 MAPT（微管相关蛋白 tau）中各种已知的常染色体显性突变得到强调，MAPT 是编码 tau 的基因，与带有 tau 包涵体的额颞叶变性 (FTLD-tau) 相关。识别影响 tau 积累的其他致病基因，包括参与蛋白质质量控​​制和 tau 清除的基因，有可能揭示以前未知的维持神经元健康的机制。基本原理 两个家庭被确定为与 VCP 中的 p.Asp395Gly 突变相关的常染色体显性痴呆症。含 Valosin 的蛋白质 (VCP) 是一种 AAA+ [与多种细胞活动相关的三磷酸腺苷 (ATPase)] 蛋白质，它利用 5'-三磷酸腺苷 (ATP) 水解产生的能量展开底物，以协助分解大分子复合物。其他 VCP 突变已在一种称为多系统蛋白病 (MSP) 的疾病中发现，该疾病与神经元 TDP-43 [TAR DNA 结合蛋白 43] 蛋白包涵体有关。p.Asp395Gly VCP 导致神经变性的机制尚不清楚。结果 两个亲属被鉴定为具有与 p.Asp395Gly VCP 突变相关的额颞叶退化的常染色体显性遗传模式。由于神经元液泡和 tau 聚集体的存在，我们将这种疾病命名为液泡性 tau 病。Tau 聚集体在形态学和生物化学上与 AD 神经原纤维缠结相似。此外，大脑中液泡和神经原纤维缠结的存在呈负相关。额叶新皮层等退化的大脑区域表现出 tau 聚集，而视觉皮层等非退化的大脑区域则表现出空泡化。为了进一步表征 p.Asp395Gly VCP 突变，我们在体外测定中评估了重组 VCP 蛋白的 ATP 酶活性。这种方法证明 p.Asp395Gly VCP 表现出 ATPase 活性的部分丧失，与 MSP 突变形成对比，MSP 突变增加 ATPase 活性。鉴于 VCP 展开蛋白质底物，我们假设 VCP 可能分解病理性 tau 聚集体。事实上，VCP 似乎部分分解了源自 AD 人脑组织的病理性 tau 聚集体，而 p.Asp395Gly 突变削弱了这种活性。针对病理性 tau 的 VCP 活性依赖于能量 (ATP)，并且需要对 tau 底物进行多聚泛素化。此外，p.Asp395Gly VCP 在 tau 聚集的细胞培养模型中的表达与细胞 tau 聚集体的增强积累有关。最后，我们生成了敲入 p.Asp395Gly 突变的小鼠，在未受到挑战时表现出最小的表型。然而，在通过将病理性 AD tau 提取物显微注射到小鼠大脑中启动 tau 聚集后，与野生型动物相比，突变的 VCP 小鼠显示出 tau 聚集增加。结论 我们描述了与神经退行性疾病相关的 VCP 部分功能丧失突变，我们将其命名为液泡性 tau 病。VCP 似乎表现出以能量和多泛素依赖性方式促进 tau 聚集体破坏的活动。此外，p.Asp395Gly VCP 突变增强了细胞培养模型系统和敲入小鼠模型中的 tau 聚集。这些结果突出了蛋白质分解在维持神经元健康方面的潜在作用。此外，我们的研究结果表明，VCP 可能为未来 AD 疗法的开发提供潜在的治疗靶点。液泡 tau 病变和 VCP 功能。tau 聚集模型，突出显示导致 AD 和 FTLD-tau 神经变性的不同机制。Tau 是一种可溶性蛋白质（绿色），在 AD 中形成高度结构化的原纤维（紫色）。Tau 聚集体也是 FTLD-tau 的标志。MAPT（编码 tau 蛋白的基因）中的常染色体显性显性 FTLD-tau 突变可以改变剪接或增强 tau 蛋白聚集，从而导致神经元和神经胶质细胞中不溶性 tau 内含物的积累。VCP（蓝色）似乎表现出针对病理性 tau 的解聚酶活性。此活动取决于能量 (ATP) 的可用性和 tau 蛋白聚集体上多聚泛素的存在。液泡性 tau 病是一种常染色体显性遗传形式的痴呆症，与 p.Asp395Gly VCP 突变（橙红色）有关。液泡性 tau 病变中的神经变性与 tau 聚集体相关，这些 tau 聚集体具有与阿尔茨海默病中所见相似的生化成分和形态。不溶性 tau 聚集体在液泡性 tau 病变中的积累似乎部分是由于与 p.Asp395Gly VCP 突变相关的 tau 分解酶功能的部分丧失。WT，野生型。阿尔茨海默病 (AD) 中的神经变性与神经原纤维缠结形式的病理性 tau 聚集体的积累密切相关。我们发现 VCP（含 valosin 蛋白）中的 p.Asp395Gly 突变与痴呆相关，其神经病理学特征为神经元空泡和神经原纤维缠结。此外，VCP 似乎在体外表现出 tau 分解酶活性，该活性受到 p.Asp395Gly 突变的损害。此外，与注射的野生型小鼠相比，脑内显微注射病理性 tau 导致敲除 p.Asp395Gly VCP 小鼠的 tau 聚集体增加。