Loss-of-function mutation in VCP mimics the characteristic pathology as in FTLD-TARDBP.
Loss-of-function mutation in VCP mimics the characteristic pathology as in FTLD-TARDBP.
复制标题
VCP 中的功能丧失突变模仿了 FTLD-TARDBP 中的特征性病理。
DOI：
10.1080/15548627.2021.1985880
复制
发表时间：
2021
期刊：
影响因子：
13.3
通讯作者：
Weihl,ConradC
中科院分区：
文献类型：
--
作者：
Wani,Abubakar;Weihl,ConradC
VCP（含缬洛辛蛋白）是 AAA+ 蛋白家族的成员，对于许多细胞过程和功能至关重要。 VCP 显性突变会导致一种罕见的神经退行性疾病，称为多系统蛋白病 (MSP)。 VCP 疾病突变引起 TARDBP/TDP-43 包含物额颞叶痴呆 (FTLD-TARDBP) 的机制尚不清楚。我们最近的工作将 VCP 活动确定为 FTLD-TARDBP 的中介。具体来说，在 vcp 条件敲除 (cKO) 小鼠中观察到脑萎缩、行为改变、神经元丢失、神经胶质增生和 TARDBP 病理学。我们还发现自噬溶酶体功能障碍、TARDBP 包涵体和泛素蛋白酶体损伤先于神经元损失。我们进一步研究了疾病相关突变 VCPR155Cinvcp 缺失小鼠的条件表达。我们观察到与 VCP 失活相似的特征，表明 VCP 突变是亚态性的。此外，vcpcKO 小鼠的蛋白质组和转录组特征与 GRN/颗粒体蛋白前体携带者相似。因此，VCP 通过多种机制对神经元存活至关重要，并且可能成为旨在恢复 FTLD-TARDBP 患者蛋白质稳态的治疗靶点。
VCP (valosin containing protein), a member of the AAA+ protein family, is critical for many cellular processes and functions. Dominant VCP mutations cause a rare neurodegenerative disease known as multisystem proteinopathy (MSP). The spectrum of mechanisms causing fronto-temporal dementia with TARDBP/TDP-43 inclusions (FTLD-TARDBP) by VCP disease mutations remains unclear. Our recent work identified VCP activity as a mediator of FTLD-TARDBP. Specifically, brain atrophy, behavioral changes, neuronal loss, gliosis, and TARDBP pathology were observed invcpconditional knockout (cKO) mice. We also found that autophago-lysosomal dysfunction, TARDBP inclusions, and ubiquitin-proteasome impairment precede neuronal loss. We further studied conditional expression of the disease-associated mutation VCPR155Cinvcp-null mice. We observed features similar to those of VCP inactivation, suggesting that VCP mutation is hypomorphic. Furthermore, proteomic, and transcriptomic signatures invcpcKO mice resemble those of GRN/Progranulin carriers. Therefore, VCP is essential for neuronal survival by several mechanisms and could be a therapeutic target aimed at restoring protein homeostasis in patients with FTLD-TARDBP.