Chilton, J. K. | bioRxiv Science

bioRxiv2025

Exploring the functions of JAKMIP1 in neuronal IL-6/STAT3 signaling and its relevance to chromosome 15q-duplication syndrome

Growing evidence supports neuroinflammation as a risk factor for neurodevelopmental and psychiatric disorders. Interleukin 6 (IL-6), a classical pro-inflammatory cytokine, has been associated with autism spectrum disorder (ASD)-related phenotypes. To better understand molecular factors that modify neuronal cytokine responses in ASD, we investigated potential roles for JAKMIP1, a gene linked to chromosome 15q-duplication syndrome (Dup15q; a form of syndromic ASD), in regulating IL-6/STAT3 signaling. We observe that JAKMIP1 deficiency impairs IL-6/STAT3 signaling and IL-6-induced neuritogenesis in SH-SY5Y cells; and discover that JAKMIP1 may regulate STAT3 expression via its C-terminus, which exhibits nucleoplasmic localization. Additionally, we find that IL-6/STAT3 signaling is altered in Dup15q hiPSCs-derived cortical neurons, which display heightened responsiveness to IL-6; though it is unclear whether and how JAKMIP1 contributes to this. Overall, our findings identify JAKMIP1 as a modulator of neuronal IL-6/STAT3 signaling and support that ASD-linked genetic variants can alter the inflammatory landscape of ASD.

neuroscience↗

bioRxiv2018

Human primary astrocytes increase basal fatty acid oxidation following recurrent low glucose to maintain intracellular nucleotide levels

Hypoglycemia is a major barrier to good glucose control in type 1 diabetes and frequent exposure to hypoglycemia can impair awareness to subsequent bouts of hypoglycemia. The neural changes that occur to reduce a persons awareness of hypoglycemia are poorly defined. Moreover, the molecular mechanisms by which glial cells contribute to hypoglycemia sensing and glucose counterregulation require further investigation. To test whether glia, specifically astrocytes, could detect changes in glucose, we utilized human primary astrocytes (HPA) and U373 astrocytoma cells and exposed them to recurrent low glucose (RLG) in vitro. This allowed measurement, with high specificity and sensitivity, of changes in cellular metabolism following RLG. We report that the AMP-activated protein kinase (AMPK) is activated over a pathophysiologically-relevant glucose concentration range. We observed an increased dependency on fatty acid oxidation for basal mitochondrial metabolism and hallmarks of mitochondrial stress including increased proton leak and reduced coupling efficiency. Relative to glucose availability, lactate release increased during low glucose but this was not modified by RLG, nor were glucose uptake or glycogen levels. Taken together, these data indicate that astrocyte mitochondria are dysfunctional following recurrent low glucose exposure, which could have implications for hypoglycemia glucose counterregulation and/or hypoglycemia awareness.

neuroscience↗