Objective: To identify a molecular substrate reflecting kinetic tremor, the core feature of essential tremor (ET)

Background: ET is one of the most common movement disorders, affecting 4% of individuals aged 40 years or older, yet the pathophysiology of ET remains unknown.

Method: We examined postmortem cerebellum in ET patients and age-matched controls to identify ET-linked molecular changes. We used molecular-driven mouse model to prove the contribution between the molecular targets and ET-like tremor. We examined the tremor characteristics and pharmacological responses of tremor in the mouse model. Targeted protein rescue and protein knockdown were performed in the tremor mice and WT mice, respectively.

Results: We identified the reduction of GluRδ2 expression in the postmortem cerebellum from ET patients (Figure 1). Grid2-dupE3 mice, a mouse model with GluRδ2 insufficiency, developed ET-like tremor that is adult-onset, chronic and progressive kinetic (action-only) tremor (Figure 2) and responsive to ET medications including primidone, propranolol and ethanol (Figure 3). GluRδ2 rescue via intra-cerebellar viral transfection confirmed the necessity and specificity of GluRδ2 in tremor generation of Grid2-dupE3 mouse model (Figure 4), while shRNA knockdown of GluRδ2 in adult, wild-type mouse cerebellum sufficiently recapitulates ET-like tremor.

Conclusion: GluRδ2 protein deficiency in the cerebellar Purkinje cells contributes to the generation of kinetic tremor, the core feature of ET.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/glur%ce%b42-protein-reduction-in-cerebellar-purkinje-cells-contributes-to-the-pathogenesis-of-essential-tremor/