Abstract：
Dominant VCP-mutations cause a variety of neurological manifestations including inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 (IBMPFD). VCP encodes a ubiquitously expressed multifunctional protein that is a member of the AAA+ protein family, implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation. The latter function accords with the presence of protein aggregates in muscle biopsy specimens derived from VCP-patients. Studying the proteomic signature of VCP-mutant fibroblasts, we identified a (pathophysiological) increase of FYCO1, a protein involved in autophagosome transport. We confirmed this finding applying immunostaining also in muscle biopsies derived from VCP-patients. Treatment of fibroblasts with arimoclomol, an orphan drug thought to restore physiologic cellular protein repair pathways, ameliorated cellular cytotoxicity in VCP-patient derived cells. This finding was accompanied by increased abundance of proteins involved in immune response with a direct impact on protein clearaqnce as well as by elevation of pro-survival proteins as unravelled by untargeted proteomic profiling. Hence, the combined results of our study reveal a dysregulation of FYCO1 in the context of VCP-etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre-clinical testing of this drug in fibroblasts.
摘要：
显性VCP突变可引起多种神经系统表现，包括包涵体肌病伴早发性Paget病和额颞叶痴呆1（IBMPFD）。VCP编码一种广泛表达的多功能蛋白，它是AAA+蛋白家族的成员，涉及从细胞器生物发生到泛素依赖性蛋白质降解的多种细胞功能。后者的功能与VCP患者肌肉活检标本中蛋白质聚集体的存在相一致。研究VCP突变成纤维细胞的蛋白质组学特征，我们发现FYCO1是一种参与自噬体转运的蛋白(病理生理)增加.我们在VCP患者的肌肉活检中也应用免疫染色证实了这一发现。用阿莫罗治疗成纤维细胞，一种孤儿药物，被认为可以恢复生理细胞蛋白质修复途径，改善VCP患者来源的细胞的细胞毒性。这一发现伴随着参与免疫反应的蛋白质丰度增加，对蛋白质清除有直接影响，以及通过非靶向蛋白质组学分析揭示的促存活蛋白质的升高。因此，我们研究的综合结果揭示了在VCP病因病理学背景下FYCO1的失调，突出显示arimoclomol作为一种潜在的药物，并在成纤维细胞中引入通过该药物的临床前测试靶向的蛋白质。
