R01NS117745

Deep Dive: Mapping the Neuropathology of Essential Tremor and Exploring the Molecular Underpinnings of Neurodegeneration

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 the 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 affect 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.

The Trustees Of Columbia University In The City Of New York

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

New York United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 357% from $1,028,252 to $4,696,438.