PROJECT SUMMARY/ ABSTRACT
Essential tremor (ET) is the most common tremor disorder, affecting 2.2% of the total US population. ET is also
a progressive disorder, with tremor becoming more severe over time. Despite its high prevalence, therapeutic
options for ET are far from satisfactory, in part due to an unclear understanding of disease mechanisms,
leaving many patients disabled. Through long-term NIH funded efforts to collect postmortem ET brains, we
have identified morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs).
Recent converging evidence of genetics and neuropathology has identified a role for abnormal endoplasmic
reticulum (ER) calcium handling in ET. Specifically, a key ER calcium channel called ryanodine receptor type 1
(RyR1), which is expressed in PCs in cerebellar cortex, undergoes site-specific phosphorylation and in this
state becomes leaky. We found that ET cerebellum has markedly increased levels of phosphorylated RyR1,
which is not seen in control or Parkinson’s cerebellum, creating a chronic ER calcium leak state in the ET
cerebellum. We established a mouse model harboring a point mutation in RyR1 that mimics constitutive site-
specific phosphorylation, recapitulating the RyR1 leaky phenotype (RyR1-S2844D “leaky” mice), and this
mouse model develops altered cerebellar physiology and progressive ET-like tremor. These findings support
that abnormal ER calcium handling contributes to tremor. However, the detailed mechanism how abnormal ER
calcium handling leads to tremor and whether its manipulation can be used to treat tremor remains unclear,
which is a major obstacle for therapy development. Towards solving this knowledge gap, we propose to test
the hypothesis that dysfunctional ER calcium handling leads to structural and physiological alterations in
cerebellum that drive tremor. In the proposed five year study, we will use both mouse models (Aim 1, Aim 2)
and postmortem human ET brains (Aim 3) to address the role of ER calcium handling for tremor generation:
Aim 1: We will determine how specific structural and physiological changes in cerebellar PCs of RyR1-leaky
mice play a role in tremor emergence and progression. Aim 2: We will determine if bi-directional modulation of
ER calcium handling alters PC physiology and tremor in RyR1-leaky mice and examine the PC specificity of
these alterations. Aim 3: We will determine whether the upstream regulators for RyR1 biochemical remodeling
and the degree of RyR1 leakiness are altered in the postmortem human ET cerebellum and correlate these
metrics with tremor severity and PC pathologic changes. These data will advance our understanding of ET
from observational studies into mechanistic insight, which will serve as scientific rationale for therapy
development.