Grant: Project Grant

Essential tremor (ET) is one of the most common neurological disorders affecting nearly 1% of the population. It causes uncontrollable shaking of multiple body parts including the hands, arms, head and legs. The disorder is quite debilitating, having an effect on the capacity of patients to perform daily activities. Not much is known about why and how ET arises in certain individuals. We know that the main brain region responsible for ET is the cerebellum which controls the coordination of movements. However, we have limited information on the role that the different cells in the cerebellum play in the disease. In the past, we have used bulk-RNA sequencing to investigate gene expression changes in the cerebellum of patients. While this provide information about the abnormal of specific genes, this method is unable to study gene expression changes in specific cell populations and lacks the required resolution to understand the role of each cell type in the disease. We will now further this work by using different more advanced methods [single-cell RNA sequencing and spatial (localized) RNA sequencing of tissue sections] to study gene expression changes in all cell populations of the cerebellum. We will also evaluate the effects of genetic risk factors on gene expression in cerebellar cells. These effects are mostly cell-type specific. Recent advances in single-cell RNA sequencing and population genetics have allowed us to link genetic events to expression events (called expression quantitative trait loci (eQTLs)) and infer the effects of genetic risk factors on gene expression in specific cells. Potential findings could guide future development including hiPSC modeling. Our ultimate goal is to identify causal cell types in the disease to develop better diagnostic tools and therapeutics to finally help patients suffering from this disease.