Essential tremor (ET) is a chronic and progressive neurological disease affecting 7 million individuals in the
US, making it the most common tremor disorder. Despite being so prevalent, its underlying patho-mechanisms
remain enigmatic. In 2003, we established the Essential Tremor Centralized Brain Repository. Meticulous
clinical phenotyping of brain donors is followed by brain harvest and rigorous postmortem characterization.
Through this mechanism, we have harvested 217 ET brains, representing by far the largest collection of ET
brains in the world. Through detailed, systematic, controlled postmortem studies, we have learned that the
major postmortem changes in ET lie in the cerebellum, centered in/around Purkinje cells. Yet, in fundamental
ways, our studies have only grazed the surface. Indeed, our studies have sampled only one parasagittal region
of the cerebellar cortex. As an organ, the cerebellum is not a unitary entity; it is heterogeneous and comprised
of well-defined anatomic and functional compartments, which are differentially involved across various disease
states. We have yet to map out the degenerative pattern seen in the ET cerebellum (Aim 1). The current
disease model is also very cerebellar-centric, and one must consider whether the problem is wider. Indeed,
there is a “tremor circuit”, the cerebello-thalamo-cortical (CTC) loop and olivo-cerebellar (OC) networks,
comprising highly organized connections between the cerebellum, deep brain structures and the motor cortex,
and between cerebellum and inferior olive; these networks have been posited to be involved in the origins and
propagation of tremor in ET. Whether the postmortem changes in ET are distributed across and/or differentially
affects these physiological networks is not known (Aim 2). Studies of ET must also move from the level of
cellular changes down to molecular events. To begin to define the molecular features of ET, over the past
several years we have explored the molecular transcriptome in ET cerebellum by RNA sequencing, which
identified dysregulation in four main biologic pathways. Thus, to complement our studies of the transcriptome,
we now propose a mass spectrometry-based proteomics approach, and partnering this with laser capture
microdissection (LCM) to target distinct neuronal populations in the tremor circuit. The creation of proteome
catalogs, comparing cases to matched controls, will uncover molecular events specifically associated with
disease (Aim 3). The proposed five-year study has three aims. AIM 1: To create a granular and refined map of
ET cerebellar neuropathology. We will determine whether and in what pattern the degenerative changes we
have documented in one region of the neocerebellum extend to other functional/anatomic cerebellar regions.
AIM 2: To determine whether the degenerative changes in ET are restricted to the cerebellum or more broadly
involve other structures in the CTC loop and OC loop. AIM 3: To use a mass spectrometry-based proteomic
approach to study protein expression in ET in an unbiased manner. We will analyze whole cerebellar cortex
tissue and partner this with LCM to target Purkinje cells as well as neurons in dentate and inferior olive nuclei.
