Thursday, December 26, 2024
12/26/2024
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.
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