Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida, United States of America.
PLoS One. 2010 Feb 8;5(2):e9104. doi: 10.1371/journal.pone.0009104.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms.
METHODOLOGY/PRINCIPAL FINDINGS: We performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300), sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008) upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03) and amygdala (p = 0.003). To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls) and found a significant upregulation of the upstream (5') exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04) of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression) in PD blood versus controls.
CONCLUSIONS/SIGNIFICANCE: The consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease.
帕金森病（PD）是一种进行性神经退行性疾病，影响全球约 500 万人。诊断仍然基于表型模式的临床依据。急需发现能够提高诊断准确性、允许疾病进展的临床前检测和跟踪的实验室标志物。这些生物标志物可能包括具有不同异构体的转录本。
方法/主要发现：我们通过 GEO 对 3 个 PD 微阵列实验进行了广泛分析，发现 RNA 剪接基因 SRRM2（或 SRm300），丝氨酸/精氨酸重复矩阵 2，是所有 3 个 PD 实验中唯一上调的基因。SRRM2 在其他神经疾病患者的血液中与健康对照组相比没有变化。通过实时 PCR，我们报告在 PD 患者的黑质中，较短的 SRRM2 转录本上调了 1.7 倍（p=0.008），而较长的转录本在黑质（p=0.03）和杏仁核（p=0.003）中下调了 0.4 倍。为了验证我们的结果并检验 PD 中可能存在的选择性剪接，我们使用 Affymetrix Exon_ST1 阵列，对 28 个人（17 个 PD 和 11 个对照）的外周血进行了独立的微阵列扫描，发现 SRRM2 的上游（5'）外显子显著上调，下游外显子下调，导致长异构体总共下调了 0.7 倍（p=0.04）。此外，我们还报告了 PD 血液与对照组相比数百个基因的显著选择性剪接（外显子表达差异）的新信息。
结论/意义：RNA 剪接因子 SRRM2 在两种不同的 PD 神经元来源和 PD 血液中一致失调，但在其他神经疾病患者的血液中没有失调，这使得 SRRM2 成为 PD 的一个强有力的候选基因，并引起了人们对 RNA 剪接在疾病中的作用的关注。
