Experimental Neurology, Department of Neurology, Goethe University Hospital, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany.
Mol Neurobiol. 2012 Aug;46(1):20-7. doi: 10.1007/s12035-012-8245-1. Epub 2012 Feb 19.
Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues.
帕金森病是第二常见的神经退行性疾病。虽然大多数病例是散发性突变,但越来越多的基因,包括 Parkin(PARK2)和 PINK1(PARK6),与该疾病有关。不同的动物模型和细胞模型,如患者皮肤成纤维细胞和重组细胞系,可作为帕金森病的模型系统。皮肤成纤维细胞呈现出具有明确突变和患者累积细胞损伤的系统。PINK1 和 Parkin 基因在人类成纤维细胞中显示出相关的表达水平,并且由于这两个基因都参与应激反应途径,我们认为成纤维细胞在评估应激源的影响等方面具有优势。此外,由于生物能量缺陷是帕金森病早期的基础,而萎缩是晚期的基础,因此使用原代细胞似乎比使用肿瘤细胞系更可取。使用源自成纤维细胞的诱导多能干细胞重新分化为多巴胺能神经元是一个额外的好处。然而,使用成纤维细胞也有一些缺点。我们研究了 PARK6 成纤维细胞,它们非常接近地反映了呼吸改变、表达谱、线粒体动力学病理学以及对蛋白酶体应激的易感性,这些在其他模型系统中已经有记录。来自 PARK2、PARK6、特发性帕金森病、阿尔茨海默病和脊髓小脑共济失调 2 型患者的成纤维细胞表现出关键神经退行性疾病基因的独特和独特的 mRNA 表达模式。因此,原代皮肤成纤维细胞是一种有用的帕金森病模型,能够作为动物突变体、转化细胞系和患者组织的补充。