An Investigation into the Varied Roles of Phosphoprotein Enriched in Astrocytes-15kD (PEA15) In Energy Metabolism, Metabolic Flexibility, and Gyrencephalic Neurodevelopment

Abstract

Phosphoprotein Enriched in Astrocytes-15kD (PEA15) is an intracellular adaptor protein that has roles in regulating important cellular processes such as apoptosis, proliferation, and glucose metabolism. PEA15 has been researched in relation to several different disease states, but most of the research has been focused on the role of PEA15 in energy metabolism, type 2 diabetes mellitus (T2DM), and in neurodegenerative diseases such as Alzheimer’s Disease (AD). Recent work has also shown that PEA15 may also play an important role in neurodevelopment, especially in gyrencephalic species. These topics will be discussed in detail in the literature review. Examining the body of work on PEA15, there are several gaps in knowledge. Our two projects aimed to investigate and clarify these gaps in knowledge. While there have been many studies investigating PEA15 in various disease states, the studies on each individual disease are scattered and relatively low in number, and often do not fully interrogate the respective mechanisms for the role of PEA15 in these disease states. In the first chapter, our study investigates the role of PEA15 in metabolic regulation and brain expression under conditions of insulin resistance. We hypothesized that the absence of PEA15 would ameliorate insulin resistance and that PEA15 expression would increase in the brain during metabolic stress. We also hypothesized that PEA15 expression in the brain would increase with insulin resistance. Using male and female wild-type (WT) and PEA15 knockout (KO) mice, the study assessed various metabolic parameters over 20 weeks. In contrast to our hypothesis, our findings indicated that absence of PEA15 may lead to exacerbated adiposity and impaired glucose tolerance, rather than improving these conditions. Additionally, our results indicated that there were sex-specific findings, with differing results between male and female mice. Male KO mice fed a chow diet had increased adiposity than their WT counterparts, while female KO mice fed a HFD exhibited greater weight gain and glucose intolerance than WT mice fed high-fat diet (HFD). There were also sex-specific differences in metabolic flexibility between chow-fed male and female KO mice. Interestingly, all KO mice had decreased rest in comparison to WT mice, suggesting that PEA15 may have a role in the regulation of sleep. Regarding brain expression of PEA15 in insulin resistance, female mice showed increased PEA15 expression in selected brain regions under HFD-feeding, whereas males did not. These findings underscore the complex, sex- specific roles of PEA15 in metabolic processes and suggest it may be a potential target for addressing obesity and type 2 diabetes. Future research will focus on PEA15’s localization and its functional implications in the brain. In our second study, we wanted to investigate another gap in knowledge in the literature. The role of PEA15 in neurodevelopment has not been investigated, but there are indications that PEA15 may play a significant role in gyrification. In the second chapter, we discuss and investigate the role of PEA15 in neurodevelopment and gyrification in a feline model with a spontaneous loss of function mutation, which leads to microcephaly and notable neurological deficits. We aimed to quantify the phenotypic differences related to neuroanatomy, gait, and developmental milestones using neurological assessments, magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS). Affected cats showed delays in developmental milestones and persistent neurological deficits, including altered gait, vision, and spinal reflexes. These were linked to brain MRI findings such as decreased white matter density and polymicrogyria, though systemic energy metabolism remained stable. Mechanistically, decreased cellular glucose uptake was observed in PEA15-deficient fibroblasts in cell culture. Overall, the findings establish a connection between PEA15 mutation and significant neuroanatomical changes, while suggesting that baseline metabolic parameters do not differ markedly in affected cats. Future research will aim to further investigate and clarify the effect of this mutation in brain glucose uptake, metabolism, and energetics. Taken together, our review of the literature indicates that more work is needed to clarify the specific roles of PEA15, especially in peripheral energy metabolism, brain energetics, and neurodevelopment. Our research opened an avenue for investigating the potential sex-specific effects of PEA15 regarding metabolism, metabolic flexibility, and circadian rhythm. Regarding neurodevelopment, we clarified the phenotypic findings in a model of gyrencephalic brain development, but further work is needed to investigate the effect of PEA15 on brain glucose uptake and cellular energetics. Future studies will focus on specific localization of PEA15 in the brain and mechanistic evaluation of the effects of PEA15 on both systemic and brain energy metabolism.