Deficiency in Parkinson's Disease risk gene CD38 as it relates to glial function: dysregulation of astrocyte genes and bioenergetics as a result of CD38 deficiency
| dc.contributor.author | Hernandez, Raymundo Daniel | en |
| dc.contributor.committeechair | Olsen, Michelle Lynne | en |
| dc.contributor.committeemember | Fox, Michael A. | en |
| dc.contributor.committeemember | Pickrell, Alicia M. | en |
| dc.contributor.committeemember | Cowell, Rita | en |
| dc.contributor.department | Graduate School | en |
| dc.date.accessioned | 2024-01-13T09:00:35Z | en |
| dc.date.available | 2024-01-13T09:00:35Z | en |
| dc.date.issued | 2024-01-12 | en |
| dc.description.abstract | Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disease and currently affects over 8 million people worldwide. The primary features of PD include cognitive, behavioral, and motor function deficits induced primarily by the progressive loss of dopaminergic neurons within the substantia nigra of the basal ganglia (BG). Motor coordination becomes severely affected over the course of the disease, causing patients to experience tremors at rest, bradykinesia, and body rigidity. The availability of treatment options has increased the quality of life for patients experiencing the early stages of PD; however, there exists no cure and treatment options are limited for those experiencing severe, advanced disease symptoms. Genetic studies in PD patients have led to the identification of causative genes, but revealed that less than 20% of cases can be attributed to monogenic variations. Evidence strongly indicates that the majority of PD cases are idiopathic and likely driven due to gene by environmental interactions. Reflective of this idea, recent research efforts have turned to genome-wide association studies (GWAS) to provide indications of gene variations, that while not causative of PD, incur increased risk within patient populations. GWAS findings play a particularly crucial role in neurodegenerative interventions, as early identification of patient risk may allow for preventative therapeutics to delay disease onset or reduce symptom severity. Amongst the many gene variants identified as incurring increased PD risk, single-nucleotide polymorphisms (SNPs) in the loci for CD38 that cause reduced gene expression are consistently identified as increasing risk. The cluster of differentiation 38 (CD38) protein serves two major roles: one as a receptor for immunological response and a second as an ectoenzyme that modulates bioenergetic functions. The particular functions of CD38 are highly relevant to neurodegenerative contexts, as changes in central nervous system (CNS) inflammatory status and means of cellular energy production typically precede pathological indications. In the brain, CD38 expression is most enriched in astrocytes in BG regions, including substantia nigra, midbrain, and striatum. However, it is not known how CD38 deficiency may contribute to astrocytic dysfunction and neuropathological features of PD. This dissertation describes how CD38 influences astrocytic gene expression and cellular bioenergetics. Astrocyte RNA was sequenced from the BG of one-year old male Cd38+/+, Cd38+/-, and Cd38-/- mice by magnetic-activated cell sorting (MACS) to acquire astrocyte isolates. Numerous differentially expressed genes (DEGs) were identified in Cd38 Cd38+/- and Cd38-/- astrocytes that relate to regulation of cellular health, responses to stress, and bioenergetic functions. GO analysis further suggested mitochondrial dysfunction in both Cd38+/- and Cd38-/- astrocytes. In a subsequent set of experiments evaluating mitochondrial function by Seahorse XF96 platform, Cd38+/- and Cd38-/- astrocytes displayed altered bioenergetic function. The results herein demonstrate that astrocytic Cd38 expression regulates cellular function and implicates transcriptional changes associated with the hallmarks of neurodegeneration. These findings serve to provide future direction for studies evaluating the relationship between CD38 function and astrocytes as it relates to neurodegenerative PD risk. | en |
| dc.description.abstractgeneral | Parkinson's disease (PD) is the second most common age-related neurodegenerative disease and currently affects over 8 million people worldwide. The primary features of PD include cognitive, behavioral, and motor function deficits induced primarily by the progressive loss of specialized neurons within the substantia nigra of the basal ganglia (BG) brain region. Motor coordination becomes severely affected over the course of the disease, causing patients to experience body tremors, slowness, and rigidity. The availability of treatment options has increased the quality of life for patients experiencing the early stages of PD; however, there exists no cure and little treatment options for those experiencing severe, advanced disease symptoms. Genetic studies in PD patients have led to the identification of causative genes, but revealed that less than 20% of cases can be attributed to specific, individual variations. Evidence strongly indicates that the majority of PD cases are likely caused by small gene changes that interact with environmental factors. Recent research efforts have turned to genome-wide association studies (GWAS) to identify these small changes, that while not causative of PD, may increase risk within patient populations. GWAS findings play a particularly crucial role in treating neurodegenerative diseases, as early identification of patient risk may allow for preventative therapeutics to slow disease onset or reduce symptom severity. Amongst the many small gene changes identified as increasing PD risk, changes in the gene CD38 that cause reduced gene expression are consistently identified as increasing risk. The cluster of differentiation 38 (CD38) protein serves two major roles: one as a receptor for immune responses and a second as an enzyme that impacts how cells produce energy. The functions of CD38 are highly relevant to neurodegenerative contexts, as changes in central nervous system (CNS) inflammatory status and means of cellular energy production typically precede disease pathology. In the brain, CD38 expression is most enriched in astrocytes, specialized brain cells that supports neurons, in regions affected by PD. However, it is not known how CD38 deficiency may contribute to astrocytic dysfunction and neuropathological features of PD. This dissertation describes how CD38 influences astrocytic gene expression and cellular bioenergetics. Astrocyte RNA was sequenced from the BG of one-year old male Cd38+/+, Cd38+/- (50% CD38 loss), and Cd38-/- (100% CD38 loss) mice by magnetic-activated cell sorting (MACS) to acquire astrocytes. Numerous changes in gene expression were identified in Cd38 Cd38+/- and Cd38-/- astrocytes that relate to regulation of cellular health, responses to stress, and energy functions. Further analysis looking at functions, suggested mitochondrial abnormalities in both Cd38+/- and Cd38-/- astrocytes. In a subsequent set of experiments evaluating mitochondrial function by Seahorse XF96 platform, Cd38+/- and Cd38-/- astrocytes displayed altered energetic function. The results herein demonstrate that astrocytic Cd38 expression regulates cellular function and implicates transcriptional changes associated with the hallmarks of neurodegeneration. These findings serve to provide future direction for studies evaluating the relationship between CD38 function and astrocytes as it relates to neurodegenerative PD risk. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:39422 | en |
| dc.identifier.uri | https://hdl.handle.net/10919/117355 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | astrocyte | en |
| dc.subject | glia | en |
| dc.subject | CD38 | en |
| dc.subject | Parkinson's disease | en |
| dc.subject | mitochondria | en |
| dc.subject | bioenergetics | en |
| dc.subject | neurodegeneration | en |
| dc.title | Deficiency in Parkinson's Disease risk gene CD38 as it relates to glial function: dysregulation of astrocyte genes and bioenergetics as a result of CD38 deficiency | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Translational Biology, Medicine and Health | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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