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Principal Investigator: Rita Marie Cowell
Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM
Fiscal Year: 2024
Award: $500,973
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Controversies exist regarding the contribution of glial cell dysregulation and inflammation to the pathogenesis
of Parkinson Disease (PD). Signs of inflammation have been detected in postmortem tissue of PD patients, and
recent evidence suggests that mutations in genes associated with familial PD can influence the function of
astrocytes and microglia. These findings, together with the existence of mutations in the HLA locus in PD
patients, have led investigators to propose an etiological role for inflammation and glial dysfunction in PD.
However, direct evidence is lacking for mechanistic links among inflammation, glial dysregulation, and the
neuronal loss characteristic of PD.
To identify potential cell-autonomous mediators of PD-relevant processes in glia, we used a bioinformatics
strategy to identify PD GWAS genes enriched in glial cells of the mouse brain. Interestingly, a small subset of
genes exhibits enrichment of expression in astrocytes. PD-linked single-nucleotide polymorphisms in one of
these genes, CD38, are associated with a ~45% reduction in CD38 transcript expression in the human brain.
Previous work has demonstrated a role for CD38 in peripheral immune cells, where it serves to regulate REDOX
balance in both intra- and extra-cellular compartments; the roles for CD38 in the brain have only recently been
explored. Preliminary experiments from our laboratory have shown that CD38 expression is enriched in
astrocytes of the human and mouse brain, NAD/NAM balance is disrupted in various regions of the CD38
knockout mouse brain, and inflammation and CD38 deficiency synergistically interact to influence motor function.
Here, we propose to use CD38 as a prototypical gene to understand ways in which glial dysfunction can give
rise to a PD-like phenotype in mice by investigating 1) the requirement for CD38 in the maintenance of REDOX
homeostasis and dopaminergic neuron function and viability in aging mice, 2) the role for CD38 in the regulation
of inflammation in the substantia nigra, and 3) the impact of CD38 modulation on the vulnerability of dopaminergic
neurons in two synucleinopathy mouse models of PD. A subset of experiments will test the involvement of
REDOX dysregulation in the changes observed in CD38-deficient mice by determining whether provision of
nicotinamide riboside, a bioavailable NAD precursor, can prevent dopaminergic oxidative stress, cell dysfunction,
and loss. Altogether, these experiments have the potential to reveal mechanistic contributors to increased
neuronal vulnerability with glial dysfunction and provide novel information about the roles for glia in maintaining
dopaminergic neuron survival in aging and disease.
Terms: <3-Pyridinecarboxamide><Acute><Age><Aging><Astrocytes><Astrocytus><Astroglia><Autopsy><Autoregulation><Behavior><Bio-Informatics><Bioavailability><Bioinformatics><Biological Availability><Body Tissues><Brain><Brain Nervous System><Causality><Cell Body><Cells><Cellular Stress><Cellular Stress Response><Characteristics><DA Neuron><DNA Damage Repair><DNA Repair><Data><Dihydronicotinamide Adenine Dinucleotide><Diphosphopyridine Nucleotide><Disease><Disorder><Dopamine><Dopamine neuron><Down-Regulation><Dysfunction><Dyskinesia Syndromes><Encephalon><Enzyme Gene><Enzymes><Equilibrium><Etiology><Evaluation><Exhibits><Extracellular Space><Functional disorder><GWA study><GWAS><Gene Expression><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Transcription><Genetic Variation><Genetic defect><Glia><Glial Cells><Health><Hereditary><Heterozygote><Homeostasis><Hortega cell><Human><Hydroxytyramine><Immune><Immune infiltrates><Immunes><Impairment><Inflammation><Inflammatory><Inherited><Injections><Intercellular Space><Investigators><KO mice><Knock-out Mice><Knockout Mice><Kolliker's reticulum><Laboratories><Lewy Bodies><Lewy neurites><Lewy-related neurites><Link><Lipopolysaccharides><Maintenance><Mediator><Messenger RNA><Mice><Mice Mammals><Microglia><Mitochondria><Modeling><Modern Man><Motor><Movement Disorder Syndromes><Movement Disorders><Murine><Mus><Mutation><NAC precursor><Nadide><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurologic><Neurological><Neurons><Niacinamide><Nicotinamide><Nicotinamide adenine dinucleotide><Nicotinamide-Adenine Dinucleotide><Nicotinamidum><Nicotinic acid amide><Nicotylamide><Non-neuronal cell><Nonneuronal cell><Null Mouse><Ontology><Oxidative Stress><PARK1 protein><PARK4 protein><Paralysis Agitans><Parkinson><Parkinson Disease><Pathogenesis><Pathway interactions><Patients><Pellagra-Preventing Factor><Peripheral><Phenotype><Physiologic Availability><Physiological Homeostasis><Physiopathology><Primary Parkinsonism><Process><Production><Proteins><QTL><Quantitative Trait Loci><RNA Expression><Reaction><Regulation><Research Personnel><Researchers><Risk-associated variant><Role><SNCA><SNCA protein><Silent Mating Type Information Regulator 2-like Proteins><Single Base Polymorphism><Single Nucleotide Polymorphism><Sir2-like Proteins><Sirtuins><Source><Substantia Nigra><Substantia nigra structure><Synapses><Synaptic><Testing><Tissues><Transcript><Transcription><Unscheduled DNA Synthesis><Vesicle><Vitamin B 3><Vitamin B3><Vitamin PP><Work><a-syn><a-synuclein><ages><alpha synuclein><alpha synuclein gene><alphaSP22><astrocytic glia><asyn><balance><balance function><carbohydrate metabolism><causation><cell stress><cell type><disease causation><disease risk><disorder risk><dopaminergic neuron><experiment><experimental research><experimental study><experiments><extracellular><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><gitter cell><heterozygosity><immune cell infiltrate><insight><mRNA><mRNA Expression><mesoglia><microglial cell><microgliocyte><mitochondrial><mitochondrial dysfunction><mouse model><murine model><necropsy><nerve cell death><nerve cell loss><nerve cement><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neuronal survival><neuropathologic><neuropathological><neuropathology><neurotransmitter release><nicotinamide ribonucleoside><nicotinamide ribose><nicotinamide riboside><nicotinamide-beta-riboside><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel><pathophysiology><pathway><perivascular glial cell><postmortem><prevent><preventing><reconstitute><reconstitution><response><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><single nucleotide variant><social role><synapse><synapse function><synaptic function><synucleinopathy><trafficking><whole genome association analysis><whole genome association studies><whole genome association study><α synuclein gene><α-syn><α-synuclein>