Gene expression analysis of the cerebellar cortex in essential tremor

Regina T Martuscello; Chloë A Kerridge; Debotri Chatterjee; Whitney G Hartstone; Sheng-Han Kuo; Peter A Sims; Elan D Louis; Phyllis L Faust

doi:10.1016/j.neulet.2019.134540

Gene expression analysis of the cerebellar cortex in essential tremor

Neurosci Lett. 2020 Mar 16:721:134540. doi: 10.1016/j.neulet.2019.134540. Epub 2019 Nov 7.

Authors

Regina T Martuscello¹, Chloë A Kerridge², Debotri Chatterjee³, Whitney G Hartstone⁴, Sheng-Han Kuo⁵, Peter A Sims⁶, Elan D Louis⁷, Phyllis L Faust⁸

Affiliations

¹ 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. Electronic address: [email protected].
² 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. Electronic address: [email protected].
³ 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. Electronic address: [email protected].
⁴ 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. Electronic address: [email protected].
⁵ 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. Electronic address: [email protected].
⁶ Department of Neurology, College of Physicians and Surgeons, Columbia University, 630 W 168th Street, BB302, New York, NY, USA; Department of Systems Biology, Columbia University Medical Center, 3960 Broadway, RM208, New York, NY, USA; Sulzberger Columbia Genome Center, Columbia University Medical Center, 1150 St. Nicholas Ave., New York, NY, USA; Department of Biochemistry & Molecular Biophysics, Columbia University Medical Center, 701 W 168th Street, New York, NY, USA. Electronic address: [email protected].
⁷ Department of Neurology, Yale School of Medicine, Yale University, 15 York Street, New Haven, CT, USA; Department of Chronic Disease Epidemiology, Yale School of Public Health, 15 York Street, Yale University, New Haven, CT, USA; Center for Neuroepidemiology and Clinical Neurological Research, Yale School of Medicine, Yale University, 15 York Street, New Haven, CT, USA. Electronic address: [email protected].
⁸ 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. Electronic address: [email protected].

Abstract

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.

Keywords: Cerebellum; Essential tremor; Gene set enrichment analysis; Purkinje cell; RNA-seq; String networks.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Cerebellar Cortex / metabolism*
Cerebellar Cortex / pathology
Databases, Genetic*
Essential Tremor / genetics*
Essential Tremor / metabolism*
Essential Tremor / pathology
Female
Follow-Up Studies
Gene Expression
Gene Regulatory Networks / physiology*
Humans
Male
Prospective Studies
Sequence Analysis, RNA / methods

Abstract

Publication types

MeSH terms

Grants and funding