Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease
Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease
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DOI：
10.1016/j.bbadis.2014.05.008
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发表时间：
2014-09-01
影响因子：
6.2
通讯作者：
Blandini, Fabio
中科院分区：
文献类型：
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作者：
Ambrosi, Giulia;Ghezzi, Cristina;Blandini, Fabio
背景资料：帕金森病（Parkinson's disease，PD）是一种复杂的疾病，研究PD发病机制的各种原因，以及确定可靠的生物标志物来诊断和监测病理进展是当前科学研究的兴趣和焦点。在外周细胞的致病机制，如成纤维细胞来源于散发性PD和年龄/性别匹配的控制，可能会产生更深入的了解影响多巴胺能神经元的赤字，并可能，新的工具适用于临床practice.Methods：原代成纤维细胞培养建立从皮肤活检。增加的易感性PD相关毒素鱼藤酮确定与凋亡和坏死特异性细胞死亡测定。通过评估泛素蛋白酶体系统（UPS）的效率和自噬标志物的蛋白水平来评价蛋白质质量控制。通过测量耗氧量和糖酵解依赖性培养基酸化来监测细胞生物能量学的变化。氧化还原状态通过检测线粒体超氧化物的产生和蛋白质和lipids.Results氧化水平确定：PD成纤维细胞表现出更高的脆弱性，由复合物I抑制剂鱼藤酮诱导的坏死细胞死亡，UPS功能降低，最大和鱼藤酮敏感的线粒体呼吸下降。自噬和氧化还原标记物没有变化detected.Conclusions：我们的研究表明，增加的敏感性鱼藤酮和存在的蛋白水解和生物能量的赤字，通常维持PD的神经退行性过程中可以检测到成纤维细胞从特发性PD患者。因此，成纤维细胞可能是一个强大的和微创的工具，以调查PD的致病机制，这可能会转化为相当大的进步，在临床管理的疾病。(C)2014爱思唯尔有限公司版权所有。
Background: Parkinson's disease (PD) is a complex disease and the current interest and focus of scientific research is both investigating the variety of causes that underlie PD pathogenesis, and identifying reliable biomarkers to diagnose and monitor the progression of pathology. Investigation on pathogenic mechanisms in peripheral cells, such as fibroblasts derived from patients with sporadic PD and age/gender matched controls, might generate deeper understanding of the deficits affecting dopaminergic neurons and, possibly, new tools applicable to clinical practice.Methods: Primary fibroblast cultures were established from skin biopsies. Increased susceptibility to the PD-related toxin rotenone was determined with apoptosis- and necrosis-specific cell death assays. Protein quality control was evaluated assessing the efficiency of the Ubiquitin Proteasome System (UPS) and protein levels of autophagic markers. Changes in cellular bioenergetics were monitored by measuring oxygen consumption and glycolysis-dependent medium acidification. The oxido-reductive status was determined by detecting mitochondrial superoxide production and oxidation levels in proteins and lipids.Results: PD fibroblasts showed higher vulnerability to necrotic cell death induced by complex I inhibitor rotenone, reduced UPS function and decreased maximal and rotenone-sensitive mitochondrial respiration. No changes in autophagy and redox markers were detected.Conclusions: Our study shows that increased susceptibility to rotenone and the presence of proteolytic and bioenergetic deficits that typically sustain the neurodegenerative process of PD can be detected in fibroblasts from idiopathic PD patients. Fibroblasts might therefore represent a powerful and minimally invasive tool to investigate PD pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease. (C) 2014 Elsevier B.V. All rights reserved.