Dissertation Defense: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
Dissertation Defense: 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
Raymundo Hernandez
Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Olsen Lab
Dec. 8, 2023 at 2 p.m.
About this Dissertation
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 disappointingly revealed that less than 20% of cases can be attributed to specific, individual mutations. 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, alterations in the gene CD38 that cause reduced expression are identified in many studies. 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 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 expressions is most associated with astrocytes, a specialized brain cell that supports neurons, in regions affected by 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 WT, HET (50% CD38 loss), and KO (100% CD38 loss) mice by magnetic-activated cell sorting (MACS) to acquire astrocytes. Numerous changes in gene expression were identified in Cd38 HET and KO 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 HET and KO astrocytes. In a subsequent set of experiments evaluating mitochondrial function by Seahorse XF96 platform, CD38 HET and KO astrocytes displayed altered energetic function compared to WTs.
The results herein, demonstrate that astrocytic Cd38 expression regulates cellular function and implicates the loss of expression as potentially harmful. These findings serve to provide future direction for studies evaluating the relationship between CD38 function and astrocytes as it relates to neurodegenerative PD risk.
More About the Candidate and Project
Education
Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate
Arizona State, B.S., Psychological Sciences
Training
Graduate Research Assistant, Olsen Lab
Mentor
Michelle L. Olsen, Ph.D., Professor and Director, School of Neuroscience
Committee Members
- Michael A. Fox, Ph.D., Dean, College of Natural Sciences, University of Massachusetts Amherst
- Alicia M. Pickrell, Ph.D., Associate Professor, Director of Graduate Studies, School of Neuroscience
- Rita M. Cowell, Ph.D., Professor, School of Medicine, University of Alabama at Birmingham
2022 VT Alliance for Neurodevelopment Research Symposium, Best Poster Presentation, 3rd place
2021 NIH Blueprint D-SPAN Award Fellow
2019 TBMH Research Symposium, Best Oral Presentation
Peer-reviewed publications
Hernandez RD, Wei X, Colafrancesco AM, Dang D, Simmons M, McMeekin LJ, Noel K, Basak S., Zhou F, Lund F, Saad J, Cowell RM, & Olsen, ML, (2023). Parkinson’s Disease associated risk gene, CD38, regulates astrocyte gene expression and bioenergetics. Manuscript in preparation.
Kowalski E.A., Soliman E., Kelly C., Gudenschwager E.K., Leonard J., Pridham K.J., Ju J., Cash A.M., Hazy A., de Jager C., Kaloss A.M., Ding H., Hernandez R.D, Coleman G.M., Wang X., Olsen M.L., Pickrell A.M., & Theus M., (2022). Monocyte recruitment and pro-inflammatory phenotypic control is governed by the ephrin type-A receptor 4 to induce neural tissue damage after trauma. JCI Insights, 7(15):e156319. doi: 10.1172/jci.insight.156319.
Haring, A.P., Thompson, E.G., Hernandez, R.D., Laheri, S., Harrigan, M.E., Lear, T., Sontheimer, H., & Johnson, B.N. (2020). 3D-Printed Multiplexed Competitive Migration Assays with Spatially Programmable Release Sources. Advanced Biosystems, 4(1), 1900225.
Kahanovitch, U., Patterson, K. C., Hernandez, R., & Olsen, M. L. (2019). Glial Dysfunction in MeCP2 Deficiency Models: Implications for Rett Syndrome. International journal of molecular sciences, 20(15), 3813. doi: https://doi.org/10.3390/ijms20153813
Holt, L. M., Hernandez, R. D., Pacheco, N. L., Ceja, B. T., Hossain, M., & Olsen, M. L. (2019). Astrocyte morphogenesis is dependent on BDNF signaling via astrocytic TrkB. T1. eLife, 8. doi: https://doi.org/10.7554/eLife.44667
Lewis, C. R., Staudinger, K., Tomek, S. E., Hernandez, R., Manning, T., & Olive, M. F. (2016). Early life stress and chronic variable stress in adulthood interact to influence methamphetamine self-administration in male rats. Behavioural Pharmacology, 27(2 and 3-Special Issue), 182-184. doi: 10.1097/FBP.0000000000000166
Watterson, L. R., Burrows, B. T., Hernandez, R. D., Moore, K. N., Grabenauer, M., Marusich, J. A., & Olive, M. F. (2015). Effects of (α-PVP) and 4-methylethcathinone (4-MEC), two synthetic cathinones commonly found in second-generation “bath salts,” on intracranial self-stimulation thresholds in rats. International Journal of Neuropsychopharmacology, 18(1). http://doi.org/10.1093/ijnp/pyu014
Presentations
2023 Society for Neuroscience
Hernandez, R.D., Wei, X., Colafrancesco, A.M., Dang, D., Simmons, M., Noel, K., Zhou, F., Lund, F., Saad, J., Cowell, R.M., & Olsen, M.L. Ectoenzyme CD38 Regulates Gene Expression and Bioenergetics in Astrocytes. Poster presentation. Society for Neuroscience November, 2023. Washington, D.C.
2022 Society for Neuroscience
Hernandez, R. D., Watsen, S.G. & Olsen, M. L. Astrocyte TrkB.T1 activation by BDNF elicits morphological responses. Poster presentation. Society for Neuroscience November, 2022. San Diego, California
2022 VT Alliance for Neurodevelopment Research Symposium
Hernandez, R. D., Holt, L. M., Pacheco, N., & Olsen, M. L. Rett Syndrome mice have aberrant astrocyte gene expression and morphological maturation during CNS refinement. Poster presentation. VT Alliance for Neurodevelopmental Research Symposium. August, 2022. Blacksburg, Virginia
2022 American Society for Neurochemistry
Hernandez, R. D., Holt, L. M., Pacheco, N., & Olsen, M. L. Rett Syndrome mice have aberrant astrocyte gene expression and morphological maturation during CNS refinement. Poster presentation. 52nd annual meeting of the Society for Neurochemistry. April, 2022. Roanoke, Virginia
2021 Virginia Tech Underrepresented Minorities Undergraduate Research Recruitment Mixer
Hernandez, R. D., Holt, L. M., Pacheco, N.L, Torres-Ceja, B., Hossain, M., & Olsen, M. L. Astrocyte morphogenesis is dependent upon BDNF/TrkB.T1 signaling. Poster presentation. 2021 Virginia Tech Underrepresented Minorities Undergraduate Research Recruitment Mixer. September, 2021. Blacksburg, Virginia.
2021 Virginia Tech School of Neuroscience Retreat
Hernandez, R. D., Holt, L. M., Pacheco, N., & Olsen, M. L. Aberrant astrocyte gene expression and maturation during CNS refinement in Rett Syndrome model mice. Oral presentation. 2nd annual Virginia Tech School of Neuroscience Research Retreat. August, 2021. Blacksburg, Virginia (virtual).
2021 XV European Meeting on Glial Cells in Health and Disease
Hernandez, R. D., Holt, L. M., Pacheco, N., & Olsen, M. L. Transcriptomic analysis across early postnatal development in healthy and Mecp2 deficient mice reveals aberrant astrocyte maturation in Rett Syndrome mice. Poster presentation. 15th European Meeting on Glial Cells in Health and Disease. July, 2021. Marseille, France (virtual).
2021 American Society for Neurochemistry
Hernandez, R. D., Holt, L. M., Pacheco, N., & Olsen, M. L. Transcriptomic analysis across early postnatal development in healthy and Mecp2 deficient mice reveals aberrant astrocyte maturation in Rett Syndrome mice. Poster presentation. 51st annual meeting of the Society for Neurochemistry. June, 2021. Virtual.
2021 Central Virginia Society for Neuroscience
Hernandez, R. D., Holt, L. M., Pacheco, N., & Olsen, M. L. Transcriptomic analysis across early postnatal development in healthy and Mecp2 deficient mice reveals aberrant astrocyte maturation in Rett Syndrome mice. Poster presentation. 2021 annual symposium for the Central Virginia Chapter of SfN. March, 2021. Virtual.
2020 Virginia Tech School of Neuroscience Retreat
Hernandez, R. D., Holt, L. M., Pacheco, N.L, Torres-Ceja, B., Hossain, M., & Olsen, M. L. BDNF: developmental driver of astrocyte morphology and maturation. Oral presentation. 1st annual Virginia Tech School of Neuroscience Research Retreat. August, 2020. Blacksburg, Virginia (virtual).
2019 Translational Biology, Medicine, and Health Research Symposium
Hernandez, R. D., Holt, L. M., Pacheco, N.L, Torres-Ceja, B., Hossain, M., & Olsen, M. L. Astrocyte morphogenesis is dependent upon BDNF/TrkB.T1 signaling. Oral and poster presentation. 2019 Translational Biology, Medicine, and Health Research Symposium. September, 2019. Blacksburg, Virginia.
2019 VT Neuroscience Research Summer Symposium
Hernandez, R. D., Holt, L. M., Pacheco, N.L, Torres-Ceja, B., Hossain, M., & Olsen, M. L. BDNF induces morphological maturation in astrocytes via TrkB.T1. Poster presentation. August, 2019. Blacksburg, Virginia.
2018 Translational Biology, Medicine, and Health Research Symposium
Hernandez, R. D., Holt, L. M., & Olsen, M. L. Developmental regulation of astrocyte morphology: BDNF and TrkB.T1. Poster presentation. 2018 Translational Biology, Medicine, and Health Research Symposium. September, 2018. Blacksburg, Virginia.
Neuroscience Postdoc and Graduate Student Association (NPGA) committee member for community outreach and diversity & inclusivity groups, 2019-2022
Video Editor for National Science Policy Network funded “Byte-sized Science” series, 2021-2022
Co-lead Virginia Tech/Fralin Biomedical Research Institute Summer Undergraduate Research Fellowship course “Preparing a Scientific Poster”, 2021
NPGA elected Graduate Student Representative, May 2018 – October 2020
School of Neuroscience “The Amazing Brain: A Hands-On Minds-On Neuroscience Experience” booth volunteer during the Virginia Tech Science Festival, October 2019
Volunteer for The Big Event community service project at Virginia Tech, April 2018