Neuronal VCP loss of function recapitulates FTLD-TDP pathology.
Neuronal VCP loss of function recapitulates FTLD-TDP pathology.
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DOI：
10.1016/j.celrep.2021.109399
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发表时间：
2021-07-20
期刊：
影响因子：
8.8
通讯作者：
Weihl CC
中科院分区：
文献类型：
--
作者：
Wani A;Zhu J;Ulrich JD;Eteleeb A;Sauerbeck AD;Reitz SJ;Arhzaouy K;Ikenaga C;Yuede CM;Pittman SK;Wang F;Li S;Benitez BA;Cruchaga C;Kummer TT;Harari O;Chou TF;Schröder R;Clemen CS;Weihl CC
VCP中的显性突变导致多系统蛋白质病（MSP）的致病机制仍不清楚，多系统蛋白质病（MSP）是一种罕见的神经退行性疾病，表现为额颞叶退行性变伴TDP-43夹杂物（FTLD-TDP）。为了探索这一点，我们在小鼠出生后前脑神经元中敲除VCP（VCP条件性敲除[cKO]）。VCP cKO小鼠具有皮质脑萎缩、神经元损失、自噬-溶酶体功能障碍和类似于FTLD-TDP病理学的TDP-43包涵体。一个单一的疾病相关的突变，VCP-R155 C，在VCP空背景的条件表达类似地概括了VCP失活和FTLD-TDP的功能，这表明MSP突变是亚型的。从遗传定义的FTLD-TDP患者的转录组和蛋白质组数据集的比较表明，颗粒蛋白前体缺乏和VCP不足导致类似的配置文件。这些数据确定了VCP依赖性功能的丧失作为FTLD-TDP的介体，并揭示了与颗粒蛋白前体缺乏症的意想不到的生化相似性。瓦尼等人证明，神经元VCP的丧失重现了小鼠中的FTLD-TDP病理学。与MSP 1相关的VCP-R155 C突变的条件表达也概括了与其亚纯功能一致的FTLD-TDP。VCP失活的转录组学和蛋白质组学特征类似于GRN功能不全患者大脑中的转录组学特征。
The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency. Wani et al. demonstrate that loss of neuronal VCP recapitulates FTLD-TDP pathology in mice. Conditional expression of a VCP-R155C mutation, associated with MSP1, also recapitulates FTLD-TDP consistent with its hypomorphic function. A transcriptomic and proteomic signature of VCP inactivation resembles a transcriptomic signature in brains of patients with GRN insufficiency.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
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影响因子：
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作者：
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DOI：
10.1016/j.bbrc.2015.06.086
发表时间：
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影响因子：
3.1
作者：
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通讯作者：
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影响因子：
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Strittmatter, Stephen M.