Guettsches Anne-Katrin, Meyer Nancy, Zahedi René P, Evangelista Teresinha, Muentefering Thomas, Ruck Tobias, Lacene Emmanuelle, Heute Christoph, Gonczarowska-Jorge Humberto, Schoser Benedikt, Krause Sabine, Hentschel Andreas, Vorgerd Matthias, Roos Andreas
Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr University Bochum, 44789 Bochum, Germany.
Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45147 Essen, Germany.
Biomedicines. 2022 Sep 30;10(10):2443. doi: 10.3390/biomedicines10102443.
Dominant -mutations cause a variety of neurological manifestations including inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 (IBMPFD). 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 -patients. Studying the proteomic signature of -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 -patients. Treatment of fibroblasts with arimoclomol, an orphan drug thought to restore physiologic cellular protein repair pathways, ameliorated cellular cytotoxicity in -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 -etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre-clinical testing of this drug in fibroblasts.
显性突变会导致多种神经学表现，包括伴有早发性佩吉特病和额颞叶痴呆1型（IBMPFD）的包涵体肌病。 编码一种普遍表达的多功能蛋白质，它是AAA +蛋白质家族的成员，参与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。后一种功能与来自 - 患者的肌肉活检标本中存在蛋白质聚集体一致。通过研究 - 突变成纤维细胞的蛋白质组学特征，我们发现参与自噬体运输的蛋白质FYCO1（在病理生理学上）增加。我们在来自 - 患者的肌肉活检中应用免疫染色也证实了这一发现。用阿利克仑莫治疗成纤维细胞，阿利克仑莫是一种被认为可恢复生理细胞蛋白质修复途径的孤儿药，可改善 - 患者来源细胞中的细胞毒性。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生存蛋白质的升高。因此，我们研究的综合结果揭示了在 - 病因病理学背景下FYCO1的失调，强调阿利克仑莫作为一种潜在药物，并介绍了该药物在成纤维细胞临床前测试中靶向的蛋白质。
