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Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson's disease.
Progress in Neurobiology ( IF 6.7 ) Pub Date : 2020-02-11 , DOI: 10.1016/j.pneurobio.2020.101772
Phillippa J Carling 1 , Heather Mortiboys 1 , Claire Green 1 , Simeon Mihaylov 1 , Cynthia Sandor 2 , Aurelie Schwartzentruber 1 , Rosie Taylor 3 , Wenbin Wei 1 , Chris Hastings 1 , Siew Wong 1 , Christine Lo 1 , Samuel Evetts 4 , Hannah Clemmens 1 , Matthew Wyles 1 , Sam Willcox 1 , Thomas Payne 1 , Rachel Hughes 1 , Laura Ferraiuolo 1 , Caleb Webber 5 , Winston Hide 6 , Richard Wade-Martins 7 , Kevin Talbot 8 , Michele T Hu 4 , Oliver Bandmann 1
Affiliation  

Mechanistic disease stratification will be crucial to develop a precision medicine approach for future disease modifying therapy in sporadic Parkinson's disease (sPD). Mitochondrial and lysosomal dysfunction are key mechanisms in the pathogenesis of sPD and therefore promising targets for therapeutic intervention. We investigated mitochondrial and lysosomal function in skin fibroblasts of 100 sPD patients and 50 age-matched controls. A combination of cellular assays, RNA-seq based pathway analysis and genotyping was applied. Distinct subgroups with mitochondrial (mito-sPD) or lysosomal (lyso-sPD) dysfunction were identified. Mitochondrial dysfunction correlated with reduction in complex I and IV protein levels. RNA-seq based pathway analysis revealed marked activation of the lysosomal pathway with enrichment for lysosomal disease gene variants in lyso-sPD. Conversion of fibroblasts to induced neuronal progenitor cells and subsequent differentiation into tyrosine hydroxylase positive neurons confirmed and further enhanced both mitochondrial and lysosomal abnormalities. Treatment with ursodeoxycholic acid improved mitochondrial membrane potential and intracellular ATP levels even in sPD patient fibroblast lines with comparatively mild mitochondrial dysfunction. The results of our study suggest that in-depth phenotyping and focussed assessment of putative neuroprotective compounds in peripheral tissue are a promising approach towards disease stratification and precision medicine in sPD.

中文翻译:

周围组织的深表型化促进了散发性帕金森氏病的机械性疾病分层。

机械疾病分层对于开发用于将来散发性帕金森氏病(sPD)的疾病改良疗法的精确医学方法至关重要。线粒体和溶酶体功能障碍是sPD发病机理中的关键机制,因此有望成为治疗干预的目标。我们调查了100 sPD患者和50个年龄匹配的对照的皮肤成纤维细胞中的线粒体和溶酶体功能。结合了细胞测定,基于RNA序列的途径分析和基因分型。确定了具有线粒体(mito-sPD)或溶酶体(lyso-sPD)功能障碍的不同亚组。线粒体功能障碍与复杂的I和IV蛋白水平降低有关。基于RNA-seq的途径分析显示,溶酶体途径的标记激活显着增强了溶酶体-sPD中的溶酶体疾病基因变异。成纤维细胞转化为诱导的神经元祖细胞并随后分化为酪氨酸羟化酶阳性神经元,证实并进一步增强了线粒体和溶酶体异常。熊去氧胆酸治疗可以改善线粒体膜电位和细胞内ATP水平,即使是在患有轻度线粒体功能障碍的sPD患者成纤维细胞系中。我们的研究结果表明,深入表型分析和集中评估周围组织中假定的神经保护性化合物,是解决sPD疾病分层和精准医学的一种有前途的方法。成纤维细胞转化为诱导的神经元祖细胞并随后分化为酪氨酸羟化酶阳性神经元,证实并进一步增强了线粒体和溶酶体异常。熊去氧胆酸治疗可以改善线粒体膜电位和细胞内ATP水平,即使是在患有轻度线粒体功能障碍的sPD患者成纤维细胞系中。我们的研究结果表明,深入表型分析和集中评估周围组织中假定的神经保护性化合物,是解决sPD疾病分层和精准医学的一种有前途的方法。成纤维细胞转化为诱导的神经元祖细胞并随后分化为酪氨酸羟化酶阳性神经元,证实并进一步增强了线粒体和溶酶体异常。熊去氧胆酸治疗甚至可以改善线粒体功能较轻的sPD患者成纤维细胞系,从而改善线粒体膜电位和细胞内ATP水平。我们的研究结果表明,深入表型分析和集中评估周围组织中假定的神经保护性化合物,是解决sPD疾病分层和精准医学的一种有前途的方法。熊去氧胆酸治疗甚至可以改善线粒体功能较轻的sPD患者成纤维细胞系,从而改善线粒体膜电位和细胞内ATP水平。我们的研究结果表明,深入表型分析和集中评估周围组织中假定的神经保护性化合物,是解决sPD疾病分层和精准医学的一种有前途的方法。熊去氧胆酸治疗甚至可以改善线粒体功能较轻的sPD患者成纤维细胞系,从而改善线粒体膜电位和细胞内ATP水平。我们的研究结果表明,深入表型分析和集中评估周围组织中假定的神经保护性化合物,是解决sPD疾病分层和精准医学的一种有前途的方法。
更新日期:2020-02-12
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