R01NS123571

Dissect the Mechanisms of Selective Regional Vulnerability in Lewy Body Dementias via Comparative snRNA-seq Analysis - Project Summary

Lewy Body Diseases (LBDs) are highly heterogeneous neurodegenerative disorders, including Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD), and Dementia with Lewy Bodies (DLB). LBDs are characterized by the abnormal aggregation of the protein alpha-synuclein in neuronal cell bodies (Lewy bodies) and neurites, which are currently considered to be the common cause of the diseases. The deposition of Lewy bodies starts in the caudal brainstem of PD but in the neocortex of DLB cases. The regional differences of initial alpha-synuclein deposition correlate with neuronal loss in the corresponding regions - dopamine neurons in the substantia nigra (SN) and neurons of unknown identity in the neocortex, and the unique clinical manifestations with a predominant motor symptom in PD, whereas early dementia in DLB.

Why some particular neurons and brain regions are affected at the disease onset, whereas the neighboring cells and regions are not? This is a fundamental question in the field of neurodegenerative diseases that this proposal will address via novel genomics technologies and bioinformatics tools.

In an initial pilot study, using single nucleus RNA-sequencing (snRNA-seq) analyses, we identified a novel disease-associated astrocyte (DAA) subpopulation and demonstrated that DAA contributed to increased inflammation, amyloid pathology, and neurodegenerative disease pathogenesis, whereas parenchymal astrocytes had compromised functionality in both Alzheimer's Disease (AD) and PD brains. Additionally, we identified three microglia subpopulations that were similar to, but with marker gene expression profiles distinct from, the conventional resting (M0), M1, and M2 activated microglia. We observed deficient microglia functionality shared across all microglia subpopulations and uniquely up-regulated inflammatory pathways in PD, suggesting common and PD-specific mechanisms of neurodegeneration. These data provide us with an exclusive opportunity to analyze the relationships between these glia subpopulations and selective regional and neuronal vulnerability in different diseases.

In Aim 1, we will identify vulnerable neuronal types in the frontal cortex (FC) and SN of patients with PD, PDD, and DLB. In Aim 2, we will test the hypothesis that astrocyte/microglia dysfunction underlies the mechanism of the selective regional vulnerability of LBD. In Aim 3, we will test the hypothesis that dysregulated interactions between neurons and astrocytes/microglia underlie the mechanism of the selective neuronal vulnerability of LBD. Our study will provide deep insights into the molecular mechanisms of selective neuronal and regional vulnerability in LBDs. Besides, our study will provide molecular biomarkers and tools for neuron cell-type-specific protection and targeted astrocyte/microglia subpopulation isolation and manipulation. Furthermore, our study will provide molecular biomarkers for distinguishing PD, PDD, and DLB, which is very important but a considerable challenge today.

Washington University

(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.

93.866 - Aging Research

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

National Institute on Aging (NIA) [HHS - NIH]

Saint Louis, Missouri 631101010 United States

Single Zip Code

Mechanisms of Selective Vulnerability in LBD and FTD (R01 Clinical Trial Not Allowed) (RFA-NS-21-007)

Amendment Since initial award the total obligations have increased 403% from $710,105 to $3,568,423.