Neurogenomics, Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America.
Neurology, Banner Sun Health Research Institute, Sun City, Arizona, United States of America.
PLoS One. 2014 May 5;9(5):e94839. doi: 10.1371/journal.pone.0094839. eCollection 2014.
The discovery and reliable detection of markers for neurodegenerative diseases have been complicated by the inaccessibility of the diseased tissue--such as the inability to biopsy or test tissue from the central nervous system directly. RNAs originating from hard to access tissues, such as neurons within the brain and spinal cord, have the potential to get to the periphery where they can be detected non-invasively. The formation and extracellular release of microvesicles and RNA binding proteins have been found to carry RNA from cells of the central nervous system to the periphery and protect the RNA from degradation. Extracellular miRNAs detectable in peripheral circulation can provide information about cellular changes associated with human health and disease. In order to associate miRNA signals present in cell-free peripheral biofluids with neurodegenerative disease status of patients with Alzheimer's and Parkinson's diseases, we assessed the miRNA content in cerebrospinal fluid and serum from postmortem subjects with full neuropathology evaluations. We profiled the miRNA content from 69 patients with Alzheimer's disease, 67 with Parkinson's disease and 78 neurologically normal controls using next generation small RNA sequencing (NGS). We report the average abundance of each detected miRNA in cerebrospinal fluid and in serum and describe 13 novel miRNAs that were identified. We correlated changes in miRNA expression with aspects of disease severity such as Braak stage, dementia status, plaque and tangle densities, and the presence and severity of Lewy body pathology. Many of the differentially expressed miRNAs detected in peripheral cell-free cerebrospinal fluid and serum were previously reported in the literature to be deregulated in brain tissue from patients with neurodegenerative disease. These data indicate that extracellular miRNAs detectable in the cerebrospinal fluid and serum are reflective of cell-based changes in pathology and can be used to assess disease progression and therapeutic efficacy.
神经退行性疾病标志物的发现和可靠检测一直受到患病组织难以获取的阻碍，例如无法对中枢神经系统进行活检或直接检测组织。起源于难以获取的组织（如大脑和脊髓内的神经元）的 RNA 具有到达外周的潜力，在那里可以进行非侵入性检测。已经发现，微泡和 RNA 结合蛋白的形成和细胞外释放能够将 RNA 从中枢神经系统的细胞带到外周，并保护 RNA 免受降解。在外周循环中可检测到的细胞外 miRNAs 可以提供与人类健康和疾病相关的细胞变化信息。为了将存在于无细胞外周生物流体中的 miRNA 信号与阿尔茨海默病和帕金森病患者的神经退行性疾病状态相关联，我们评估了来自具有完整神经病理学评估的死后受试者的脑脊液和血清中的 miRNA 含量。我们使用下一代小 RNA 测序（NGS）对 69 名阿尔茨海默病患者、67 名帕金森病患者和 78 名神经正常对照者的脑脊液和血清中的 miRNA 含量进行了分析。我们报告了每个检测到的 miRNA 在脑脊液和血清中的平均丰度，并描述了 13 种新鉴定的 miRNA。我们将 miRNA 表达的变化与疾病严重程度的各个方面相关联，如 Braak 阶段、痴呆状态、斑块和缠结密度以及路易体病理学的存在和严重程度。在外周无细胞脑脊液和血清中检测到的许多差异表达的 miRNA 以前在文献中报道过，在神经退行性疾病患者的脑组织中存在失调。这些数据表明，在外周脑脊液和血清中可检测到的细胞外 miRNAs 反映了病理学中基于细胞的变化，可以用于评估疾病进展和治疗效果。
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