Martuscello Regina T, Kerridge Chloë A, Chatterjee Debotri, Hartstone Whitney G, Kuo Sheng-Han, Sims Peter A, Louis Elan D, Faust Phyllis L
Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital, 630 W 168th Street, P&S 15-405, New York, NY, USA; College of Physicians and Surgeons, Columbia University Medical Center and the New York Presbyterian Hospital, 630 W 168th Street, New York, NY, USA.
College of Physicians and Surgeons, Columbia University Medical Center and the New York Presbyterian Hospital, 630 W 168th Street, New York, NY, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University, 630 W 168th Street, BB302, New York, NY, USA.
Neurosci Lett. 2020 Mar 16;721:134540. doi: 10.1016/j.neulet.2019.134540. Epub 2019 Nov 7.
Essential tremor (ET) is one of the most common neurological diseases, with a central feature of an 8-12 Hz kinetic tremor. While previous postmortem studies have identified a cluster of morphological changes in the ET cerebellum centered in/around the Purkinje cell (PC) population, including a loss of PCs in some studies, the underlying molecular mechanisms for these changes are not clear. As genomic studies of ET patients have yet to identify major genetic contributors and animal models that fully recapitulate the human disease do not yet exist, the study of human tissue is currently the most applicable method to gain a mechanistic insight into ET disease pathogenesis. To begin exploration of an underlying molecular source of ET disease pathogenesis, we have performed the first transcriptomic analysis by direct sequencing of RNA from frozen cerebellar cortex tissue in 33 ET patients compared to 21 normal controls. Principal component analysis showed a heterogenous distribution of the expression data in ET patients that only partially overlapped with control patients. Differential expression analysis identified 231 differentially expressed gene transcripts ('top gene hits'), a subset of which has defined expression profiles in the cerebellum across neuronal and glial cell types but a largely unknown relationship to cerebellar function and/or ET pathogenesis. Gene set enrichment analysis (GSEA) identified dysregulated pathways of interest and stratified dysregulation among ET cases. By GSEA and mining curated databases, we compiled major categories of dysregulated processes and clustered string networks of known interacting proteins. Here we demonstrate that these 'top gene hits' contribute to regulation of four main biological processes, which are 1) axon guidance, 2) microtubule motor activity, 3) endoplasmic reticulum (ER) to Golgi transport and 4) calcium signaling/synaptic transmission. The results of our transcriptomic analysis suggest there is a range of different processes involved among ET cases, and draws attention to a particular set of genes and regulatory pathways that provide an initial platform to further explore the underlying biology of ET.
特发性震颤（ET）是最常见的神经疾病之一，其主要特征是8 - 12赫兹的运动性震颤。虽然先前的尸检研究已经确定ET患者小脑存在以浦肯野细胞（PC）群体为中心/周围的一系列形态学变化，包括在一些研究中PC的丢失，但这些变化的潜在分子机制尚不清楚。由于对ET患者的基因组研究尚未确定主要的遗传因素，且尚未存在完全重现人类疾病的动物模型，目前对人体组织的研究是深入了解ET疾病发病机制的最适用方法。为了开始探索ET疾病发病机制的潜在分子来源，我们对33例ET患者与21例正常对照的冷冻小脑皮质组织RNA进行了直接测序，首次进行了转录组分析。主成分分析显示ET患者表达数据呈异质性分布，仅部分与对照患者重叠。差异表达分析确定了231个差异表达的基因转录本（“顶级基因命中”），其中一部分在小脑的神经元和神经胶质细胞类型中具有特定的表达谱，但与小脑功能和/或ET发病机制的关系很大程度上未知。基因集富集分析（GSEA）确定了感兴趣的失调途径，并对ET病例中的失调进行了分层。通过GSEA和挖掘精心策划的数据库，我们整理了失调过程的主要类别，并聚类了已知相互作用蛋白质的字符串网络。在这里，我们证明这些“顶级基因命中”有助于调节四个主要生物学过程，即1）轴突导向，2）微管运动活性，3）内质网（ER）到高尔基体运输，以及4）钙信号传导/突触传递。我们的转录组分析结果表明ET病例涉及一系列不同的过程，并提请注意一组特定的基因和调节途径，这些为进一步探索ET的潜在生物学特性提供了一个初始平台。
