Department of Neuroscience, University of California San Diego, 9500 Gilman Dr., MTF 344 MC0624, La Jolla, CA, 92093-0624, USA.
Department of Pathology, University of California San Diego, 9500 Gilman Dr., MTF 344 MC0624, La Jolla, CA, 92093-0624, USA.
Mol Neurobiol. 2019 Oct;56(10):7003-7021. doi: 10.1007/s12035-019-1577-3. Epub 2019 Apr 9.
Multiple systems atrophy (MSA) is a rare neurodegenerative disorder characterized by the accumulation of α-synuclein in glial cells and neurodegeneration in the striatum, substantia nigra, and cerebellum. Aberrant miRNA regulation has been associated with neurodegeneration, including alterations of specific miRNAs in brain tissue, serum, and cerebrospinal fluid from MSA patients. Still, a causal link between deregulation of miRNA networks and pathological changes in the transcriptome remains elusive. We profiled ~ 800 miRNAs in the striatum of MSA patients in comparison to healthy individuals to identify specific miRNAs altered in MSA. In addition, we performed a parallel screening of 700 transcripts associated with neurodegeneration to determine the impact of miRNA deregulation on the transcriptome. We identified 60 miRNAs with abnormal levels in MSA brains that are involved in extracellular matrix receptor interactions, prion disease, inflammation, ubiquitin-mediated proteolysis, and addiction pathways. Using the correlation between miRNA expression and the abundance of their known targets, miR-124-3p, miR-19a-3p, miR-27b-3p, and miR-29c-3p were identified as key regulators altered in MSA, mainly contributing to neuroinflammation. Finally, our study also uncovered a potential link between Alzheimer's disease (AD) and MSA pathologies that involves miRNAs and deregulation of BACE1. Our results provide a comprehensive appraisal of miRNA alterations in MSA and their effect on the striatal transcriptome, supporting that aberrant miRNA expression is highly correlated with changes in gene transcription associated with MSA neuropathology, in particular those driving inflammation, disrupting myelination, and potentially impacting α-synuclein accumulation via deregulation of autophagy and prion mechanisms.
多系统萎缩症（MSA）是一种罕见的神经退行性疾病，其特征是胶质细胞中α-突触核蛋白的积累和纹状体、黑质和小脑的神经退行性变。异常的 miRNA 调节与神经退行性变有关，包括脑组织、血清和 MSA 患者脑脊液中特定 miRNA 的改变。然而，miRNA 网络的失调与转录组的病理变化之间的因果关系仍然难以捉摸。我们对 MSA 患者的纹状体中的~800 个 miRNA 进行了分析，以与健康个体进行比较，以确定 MSA 中改变的特定 miRNA。此外，我们还平行筛选了与神经退行性变相关的 700 个转录本，以确定 miRNA 失调对转录组的影响。我们确定了 60 个在 MSA 大脑中异常表达的 miRNA，它们参与细胞外基质受体相互作用、朊病毒病、炎症、泛素介导的蛋白水解和成瘾途径。利用 miRNA 表达与已知靶基因丰度之间的相关性，鉴定出 miR-124-3p、miR-19a-3p、miR-27b-3p 和 miR-29c-3p 是 MSA 中改变的关键调节因子，主要导致神经炎症。最后，我们的研究还揭示了 AD 和 MSA 病理学之间的潜在联系，涉及 miRNA 和 BACE1 的失调。我们的结果全面评估了 MSA 中的 miRNA 改变及其对纹状体转录组的影响，支持异常的 miRNA 表达与与 MSA 神经病理学相关的基因转录变化高度相关，特别是那些驱动炎症、破坏髓鞘形成、并通过自噬和朊病毒机制的失调潜在地影响α-突触核蛋白积累的变化。
