Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations.
Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations.
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DOI：
10.1186/1471-2164-12-527
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发表时间：
2011-10-27
期刊：
影响因子：
4.4
通讯作者：
Rademakers R
中科院分区：
文献类型：
--
作者：
Kocerha J;Kouri N;Baker M;Finch N;DeJesus-Hernandez M;Gonzalez J;Chidamparam K;Josephs KA;Boeve BF;Graff-Radford NR;Crook J;Dickson DW;Rademakers R
额颞叶变性（FTLD）是一种进行性神经退行性疾病，可通过遗传或散发机制触发。microRNA（miRNAs）在疾病发病机制中的广泛表达和强大的调控作用日益明显，已成为主要的治疗焦点。在这里，我们研究了miRNAs在伴有TAR DNA结合蛋白43病理（FTLD-TDP）的FTLD患者中的作用，该病理是由颗粒蛋白前体（PGRN）基因突变引起的。使用miRNA阵列分析，我们鉴定了20种miRNA，当与32名没有明显遗传异常的FTLD-TDP患者相比时，8名携带PGRN突变的FTLD-TDP患者的额叶皮质中显示出最大的失调证据（未校正的P < 0.05）。定量实时PCR（qRT-PCR）分析提供了技术验证的差异表达的20个microRNA在额叶皮层中的9。另外的qRT-PCR分析显示，9种miRNA中的5种（miR-922、miR-516 a-3 p、miR-571、miR-548 b-5 p和miR-548 c-5 p）在PGRN突变携带者的小脑组织样品中也显著失调（未校正的P < 0.05），与PGRN水平的全身性降低一致。我们开发了5个候选miRNAs的基因靶点列表，并在报道的FTLD mRNA研究中发现18个基因失调，在受影响的皮质和小脑组织中表现出反相关的miRNA-mRNA模式。其中一个靶点是脑特异性血管生成抑制剂3，它最近被确定为突触生物学中的重要参与者。我们的研究表明，miRNA可能有助于PGRN突变引起的FTLD-TDP的发病机制，并为未来潜在的治疗选择提供了新的见解。
Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (PGRN) gene. Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying PGRN mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of PGRN mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology. Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and provides new insight into potential future therapeutic options.
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影响因子：
56.9
作者：
Carninci, P;Kasukawa, T;Hayashizaki, Y
通讯作者：
Hayashizaki, Y
影响因子：
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DOI：
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发表时间：
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