Paul Sharan, Dansithong Warunee, Gandelman Mandi, Figueroa Karla P, Scoles Daniel R, Pulst Stefan M
From the Department of Neurology, University of Utah.
Neurol Genet. 2024 Mar 28;10(2):e200144. doi: 10.1212/NXG.0000000000200144. eCollection 2024 Apr.
Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated in spinocerebellar ataxia type 2 (SCA2). SCA2, a dominantly inherited progressive neurodegenerative polyglutamine (polyQ) disease, is caused by a CAG repeat expansion in the ataxin-2 () gene. In this study, we determined miRNA transcriptomes in SCA2-BAC- transgenic mice.
We assessed the expression of miRNAs in SCA2 transgenic mouse cerebella using the HiSeq Illumina sequencer. We used the miRNA target filter tool in Qiagen Ingenuity Pathway Analysis (IPA) to identify target genes of differentially expressed miRNAs (DEmiRs) within in the SCA2 mouse transcriptomes and then performed pathway analyses.
Our analysis revealed significant changes in the expression levels of multiple miRNAs in mice with SCA2. We identified 81 DEmiRs in mice with SCA2, with 52 miRNAs upregulated and 29 miRNAs downregulated after onset of rotarod deficit. Subsequent IPA processing enabled us to establish connections between these DEmiRs and specific biological regulatory functions. Furthermore, by using the IPA miRNA target filter, we identified target genes of DEmiRs in the SCA2-BAC- transcriptome data set and demonstrated their significant impact on several biological functional and disease pathways.
Our study establishes the role of both DEmiRs and their targets in SCA2 pathogenesis. By expressing mutant ATXN2 under the control of its endogenous regulatory elements in the SCA2-BAC- mouse model we identified a set of DEmiRs that are shared across multiple neurodegenerative diseases including other SCAs, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). There was a significant overlap of both DEmiRs and their targets of BAC- transcriptomes in dysregulated pathways that characterize SCA2. This observation also extended to dysregulated pathways in ALS, AD, and PD. DEmiRs identified in this study may represent therapeutic targets for neurodegeneration or lead to biomarkers for characterizing various neurodegenerative diseases.
微小RNA（miRNA）对多种神经退行性疾病中基因表达的调控至关重要，但尚未在2型脊髓小脑共济失调（SCA2）中对miRNA进行研究。SCA2是一种显性遗传的进行性神经退行性多聚谷氨酰胺（polyQ）疾病，由ataxin-2（）基因中的CAG重复扩增引起。在本研究中，我们测定了SCA2-BAC-转基因小鼠中的miRNA转录组。
我们使用Illumina HiSeq测序仪评估SCA2转基因小鼠小脑中小RNA的表达。我们使用Qiagen Ingenuity Pathway Analysis（IPA）中的miRNA靶标筛选工具来识别SCA2小鼠转录组中差异表达的miRNA（DEmiR）的靶基因，然后进行通路分析。
我们的分析揭示了SCA2小鼠中多种miRNA表达水平的显著变化。我们在SCA2小鼠中鉴定出81个DEmiR，在转棒试验缺陷出现后，有52个miRNA上调，29个miRNA下调。随后的IPA分析使我们能够建立这些DEmiR与特定生物调节功能之间的联系。此外，通过使用IPA miRNA靶标筛选工具，我们在SCA2-BAC-转录组数据集中鉴定了DEmiR的靶基因，并证明了它们对几种生物学功能和疾病通路的显著影响。
我们的研究确定了DEmiR及其靶标在SCA2发病机制中的作用。通过在SCA2-BAC-小鼠模型中其内源调控元件的控制下表达突变型ATXN2，我们鉴定出一组在包括其他脊髓小脑共济失调、阿尔茨海默病（AD）、帕金森病（PD）和肌萎缩侧索硬化症（ALS）在内的多种神经退行性疾病中共享的DEmiR。在表征SCA2的失调通路中，DEmiR及其BAC-转录组靶标存在显著重叠。这一观察结果也扩展到ALS、AD和PD的失调通路。本研究中鉴定出的DEmiR可能代表神经退行性变的治疗靶点，或导致用于表征各种神经退行性疾病生物标志物。
