Abstract
Essential tremor (ET) is a common, progressive neurological disease characterized by an 8-12-Hz kinetic tremor. Despite its high prevalence, the patho-mechanisms of tremor in ET are not fully known. Through comprehensive studies in postmortem brains, we identified major morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs), suggesting that PC damage is central to ET pathogenesis. We previously performed a transcriptome analysis in ET cerebellar cortex, identifying candidate genes and several dysregulated pathways. To directly target PCs, we purified RNA from PCs isolated by laser capture microdissection and performed the first ever PC-specific RNA-sequencing analysis in ET versus controls. Frozen postmortem cerebellar cortex from 24 ETs and 16 controls underwent laser capture microdissection, obtaining ≥2000 PCs per sample. RNA transcriptome was analyzed via differential gene expression, principal component analysis (PCA), and gene set enrichment analyses (GSEA). We identified 36 differentially expressed genes, encompassing multiple cellular processes. Some ET (13/24) had greater dysregulation of these genes and segregated from most controls and remaining ETs in PCA. Characterization of genes/pathways enriched in this PCA and GSEA identified multiple pathway dysregulations in ET, including RNA processing/splicing, synapse organization/ion transport, and oxidative stress/inflammation. Furthermore, a different set of pathways characterized marked heterogeneity among ET patients. Our data indicate a range of possible mechanisms for the pathogenesis of ET. Significant heterogeneity among ET combined with dysregulation of multiple cellular processes supports the notion that ET is a family of disorders rather than one disease entity.