Subcategory: Physiology and Health
Room: Exhibit Hall
Ana Sofía Vargas Virella - Pontifical Catholic University of Puerto Rico
Co-Author(s): Katherine García Cortés, Pontifical Catholic University of Puerto Rico, Ponce, PR; Emmanuel Cruz, Pontifical Catholic University of Puerto Rico, Ponce, PR
Angelman Syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioral abnormalities. AS is caused by a loss of function of the maternally expressed and paternally imprinted UBE3A gene. No specific treatment is currently available for AS, however, recent studies have identified brain metabolism as a new method of treatment for neurodevelopmental disorders. Although AS has been associated with hippocampal mitochondrial dysfunction, the specific metabolic pathways affected by this disorder remain poorly understood. In this study, we hypothesize that a deficiency of UBE3A leads to astrocytic and neuronal metabolic impairments in the AS brain. To address this hypothesis, we measured the levels of monocarboxylate transporters (MCT2 and MCT4) and lactate dehydrogenases (LDHA and LDHB) in the frontal lobe cortex, hippocampus and cerebellum of a mouse model that carries the UBE3A mutation and mimics the symptoms associated with AS. We found a strong trend of MCT2 upregulation in the frontal lobe cortex of AS mice, a structure associated with cognitive skills and long-term memory storage. Additionally, a significant difference was observed in levels of LDHB in the cerebellum as AS mice expressed less LDHB in this structure when compared to their WT counterparts. This area is primarily responsible for motor learning. Finally, no significant difference was discovered in any of the lactate metabolism markers in the hippocampus. These results suggest that the transport and use of lactate is affected in neurons of key brain regions in the AS brain. Further studies are required to examine whether modulation of these markers can rescue the behavioral deficits found in AS mice.References:1.Alberini, C. M., Cruz, E., Descalzi, G., Bessières, B., & Gao, V. (2018). Astrocyte glycogen and lactate: New insights into learning and memory mechanisms. Glia, 66(6), 1244–1262. https://doi.org/10.1002/glia.232502.Contreras-Baeza, Y., Sandoval, P. Y., Alarcón, R., Galaz, A., Cortés-Molina, F., Alegría, K., Baeza-Lehnert, F., Arce-Molina, R., Guequén, A., Flores, C. A., San Martín, A., & Barros, L. F. (2019). Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments. The Journal of biological chemistry, 294(52), 20135–20147. https://doi.org/10.1074/jbc.RA119.0090933.Elgersma, Y., & Sonzogni, M. (2021). UBE3A reinstatement as a disease-modifying therapy for Angelman syndrome. Developmental medicine and child neurology, 63(7), 802–807. https://doi.org/10.1111/dmcn.148314.Hoshino, D., Setogawa, S., Kitaoka, Y., Masuda, H., Tamura, Y., Hatta, H., & Yanagihara, D. (2016). Exercise-induced expression of monocarboxylate transporter 2 in the cerebellum and its contribution to motor performance. Neuroscience letters, 633, 1–6. https://doi.org/10.1016/j.neulet.2016.09.0125.Maranga, C., Fernandes, T. G., Bekman, E., & da Rocha, S. T. (2020). Angelman syndrome: a journey through the brain. The FEBS journal, 287(11), 2154–2175. https://doi.org/10.1111/febs.15258
Funder Acknowledgement(s): This work was supported by PR-LSAMP. Funding was provided by a NARSAD grant to E. Cruz.
Faculty Advisor: Emmanuel Cruz, Ph.D., firstname.lastname@example.org
Role: My contribution to this project was to perform the necessary experiments and data analysis. Firstly, I dissected postmortem mice to harvest their brains and a homogenizer was used to create a uniform and consistent sample for western blots. Consequently, I performed the western blots by using gel electrophoresis to separate the sample's proteins. The separated proteins were then transferred to the surface of a membrane and this membrane was exposed to an antibody specific to the target protein. In this case, I exposed the membranes to LDHA, LDHB, MCT2 and MCT4. The membrane was also exposed to a secondary antibody, which binds to the primary antibody and allows us to visualize whether the protein of interest is expressed in this sample and have an idea of how abundant it is. After all the necessary washes were performed, the membrane was revealed using a chemiluminescence machine. After the data was collected, I performed the data analysis.