Department of (Neuro)Pathology Amsterdam Neuroscience, Amsterdam UMC Location University of Amsterdam, Amsterdam, The Netherlands.
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Neuropathol Appl Neurobiol. 2023 Feb;49(1):e12864. doi: 10.1111/nan.12864. Epub 2022 Nov 26.
Parkinson's disease (PD) is a progressive and age-dependent neurodegenerative disease characterised clinically by a variety of motor symptoms and cognitive impairment. PD was initially considered to be a grey matter disease; however, recently, evidence has emerged that white matter changes in PD precede the neuronal loss seen in the grey matter. The cause of these initial white matter changes is yet to be elucidated. Here, we explored whether dysregulated miRNAs and their target mRNA could provide insight into the underlying mechanisms of early white matter changes in PD.
We analysed the expression of miRNAs in three different stages of PD through RNA-sequencing and validated the differential expression of miRNAs through quantitative reverse transcription polymerase chain reaction. With bioinformatic analyses, we predicted target genes of dysregulated miRNAs and investigated their biomarker potential. Finally, in vitro, we confirmed the targetting of the gene SIRT1 by miR-543.
We identified 12 dysregulated miRNAs in PD and found that miR-543 holds potential as a biomarker for late-stage PD with dementia. We report upregulation of miR-543 in early PD white matter tissue and downregulation of SIRT1. In vitro experiments showed that the upregulation of miR-543 results in the downregulation of SIRT1 in the white matter, but not in the grey matter.
We validated SIRT1 as a target of miR-543 in the brain and showed its function as a potential biomarker. Our results highlight the idea that dysregulation of miR-543 in early PD white matter, resulting in the dysregulation of SIRT1, potentially influencing the early white matter changes observed in PD.
帕金森病（PD）是一种进行性和年龄相关的神经退行性疾病，临床上表现为多种运动症状和认知障碍。PD 最初被认为是一种灰质疾病；然而，最近有证据表明，PD 中的白质变化先于灰质中的神经元丢失。这些初始白质变化的原因尚未阐明。在这里，我们探讨了失调的 miRNA 及其靶 mRNA 是否能为 PD 早期白质变化的潜在机制提供深入了解。
我们通过 RNA 测序分析了 PD 的三个不同阶段的 miRNA 表达，并通过定量逆转录聚合酶链反应验证了 miRNA 的差异表达。通过生物信息学分析，我们预测了失调 miRNA 的靶基因，并研究了它们的生物标志物潜力。最后，在体外，我们通过 miR-543 证实了基因 SIRT1 的靶定。
我们在 PD 中发现了 12 个失调的 miRNA，并发现 miR-543 可能是痴呆晚期 PD 的生物标志物。我们报告说，在早期 PD 白质组织中 miR-543 上调，而 SIRT1 下调。体外实验表明，miR-543 的上调导致白质中 SIRT1 的下调，但在灰质中没有。
我们验证了 SIRT1 是 miR-543 在大脑中的靶标，并表明其作为潜在生物标志物的功能。我们的结果强调了这样一种观点，即 PD 早期白质中 miR-543 的失调导致 SIRT1 的失调，可能影响 PD 中观察到的早期白质变化。
