Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy.
Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy.
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DOI：
10.1371/journal.pone.0122888
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kimonis VE
中科院分区：
文献类型：
--
作者：
Nalbandian A;Llewellyn KJ;Nguyen C;Yazdi PG;Kimonis VE
包含Valosin的蛋白（VCP）基因的突变引起遗传性包涵体肌病（hIBM），与佩吉特骨病（PDB）、额颞叶痴呆（FTD）相关，最近被称为多系统蛋白病（MSP）。受影响的个体表现出肩胛翼，并死于进行性肌肉无力，心脏和呼吸衰竭，通常在40多岁至50多岁。在组织学上，患者显示出肌肉中存在镶边空泡和TAR DNA结合蛋白43（TDP-43）阳性的大的泛素化包涵体。我们已经产生了一个VCPR 155 H/+小鼠模型，该模型概括了通常在VCP疾病患者中观察到的疾病表型和受损的自噬。自噬修饰剂，如雷帕霉素和氯喹，在药理学剂量，先前已显示改变自噬通量。在本文中，我们报告了给予雷帕霉素（雷帕霉素（mTOR）信号通路的机制靶点的特异性抑制剂）和氯喹（一种溶酶体抑制剂，通过在溶酶体中积累来逆转自噬，负责阻断20个月大的VCPR 155 H/+小鼠中的自噬）的结果。雷帕霉素处理的小鼠表现出肌肉性能、四头肌组织学分析和泛素拯救、TDP-43病理学和缺陷性自噬的显著改善，如LC 3-I/II、p62/SQSTM 1、视神经磷酸酶的蛋白表达水平降低和抑制mTORC 1底物所示。相反，氯喹处理的VCPR 155 H/+小鼠显示进行性肌无力、TDP-43的细胞质蓄积、泛素阳性包涵体和增加的LC 3-I/II、p62/SQSTM 1和视神经磷酸酶表达水平。我们的体外患者成肌细胞研究用雷帕霉素处理证明了自噬标志物的总体改善。靶向mTOR通路改善了越来越多的疾病，这些发现表明，VCP疾病和相关的神经退行性多系统蛋白质病现在可以被列为可能通过雷帕霉素类似物改善的疾病。
Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion body myopathy (hIBM) associated with Paget disease of bone (PDB), frontotemporal dementia (FTD), more recently termed multisystem proteinopathy (MSP). Affected individuals exhibit scapular winging and die from progressive muscle weakness, and cardiac and respiratory failure, typically in their 40s to 50s. Histologically, patients show the presence of rimmed vacuoles and TAR DNA-binding protein 43 (TDP-43)-positive large ubiquitinated inclusion bodies in the muscles. We have generated a VCPR155H/+ mouse model which recapitulates the disease phenotype and impaired autophagy typically observed in patients with VCP disease. Autophagy-modifying agents, such as rapamycin and chloroquine, at pharmacological doses have previously shown to alter the autophagic flux. Herein, we report results of administration of rapamycin, a specific inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, and chloroquine, a lysosomal inhibitor which reverses autophagy by accumulating in lysosomes, responsible for blocking autophagy in 20-month old VCPR155H/+ mice. Rapamycin-treated mice demonstrated significant improvement in muscle performance, quadriceps histological analysis, and rescue of ubiquitin, and TDP-43 pathology and defective autophagy as indicated by decreased protein expression levels of LC3-I/II, p62/SQSTM1, optineurin and inhibiting the mTORC1 substrates. Conversely, chloroquine-treated VCPR155H/+ mice revealed progressive muscle weakness, cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-I/II, p62/SQSTM1, and optineurin expression levels. Our in vitro patient myoblasts studies treated with rapamycin demonstrated an overall improvement in the autophagy markers. Targeting the mTOR pathway ameliorates an increasing list of disorders, and these findings suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs.
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