Biology subjects

Devanathan, V.

Publications and source records attributed to Devanathan, V..

3 recordsLinked to original sources

bioRxiv2026

Hyperglycemia transcriptionally regulates the paranodal protein (Caspr1) in retinal neurons and modulates neurite extension

Hyperglycemia is a hallmark of diabetes, affecting neuronal structure and function by altering molecular signalling pathways. Here, we explore the role of hyperglycemia in regulating Caspr1 expression and its downstream effects on neurite outgrowth. Caspr1, a critical protein implicated in neurodegenerative diseases, was found to be significantly downregulated in N2a and 661W cell lines cultured under hyperglycemic conditions (25mM glucose) and, as a result, promoted neurite outgrowth. Knockout of Caspr1 using CRISPR-Cas9 further confirmed its inhibitory role on neurite outgrowth, as Caspr1-deficient cells exhibited enhanced neurite elongation. Caspr1 downregulation was mediated by decreased expression of C/EBP, a key transcription factor with a binding site on the Caspr1 promoter. Overexpression of C/EBP restored Caspr1 promoter activity and mRNA levels, establishing C/EBP as a critical regulator. Additionally, hyperglycemia was observed to inhibit Akt phosphorylation, which further contributed to Caspr1 downregulation. Adding insulin to the culture medium under hyperglycemic conditions shows inhibition of Akt phosphorylation and downregulation of Caspr1, resulting in a shorter length of neurites in retinal neurons. In vivo, studies in diabetic mouse models and diabetic patient samples demonstrated reduced expression of Caspr1 in retinal tissues. These results suggest that hyperglycemia regulates Caspr1 expression through Akt and C/EBP pathways, promoting neurite outgrowth in retinal neurons. In contrast, adding insulin to the medium under hyperglycemia downregulates the Caspr1 expression and reduces neurite length in retinal neurons. Targeting this pathway may offer new therapeutic approaches to mitigate neurodegeneration in diabetic retinopathy.

cell biology↗

bioRxiv2026

p62/SQSTM1 selectively supports starvation-induced autophagy in N2a neuroblastoma cells

Autophagy is a critical cellular process that maintains homeostasis and enables adaptation to metabolic stress. The selective autophagy receptor p62/SQSTM1 has been implicated in multiple aspects of autophagy regulation; however, its specific contribution to basal versus stress-induced autophagic flux remains incompletely defined, particularly in neuronal cells. In this study, we investigated the role of p62 in regulating basal and starvation-induced autophagy using a CRISPR-Cas9-generated p62 knockout (p62-/-) neuroblastoma (N2a) cell model. Autophagic flux was quantified by measuring LC3-II accumulation in the presence and absence of the lysosomal inhibitor bafilomycin A1. Under nutrient-replete conditions, basal autophagic flux was comparable between wild-type and p62-deficient cells, indicating that p62 is dispensable for constitutive autophagy. In contrast, starvation robustly increased autophagic flux in wild-type cells but failed to do so in p62-/- cells, demonstrating a requirement for p62 in starvation-induced autophagy. Consistent with a stress-responsive role, p62 protein levels increased during starvation in wild-type cells under lysosomal inhibition, reflecting enhanced p62 expression rather than impaired degradation. Together, these findings reveal a context-dependent function for p62 in neuronal autophagy, whereby p62 is essential for mounting an effective autophagic response to nutrient deprivation but is not required for basal autophagic turnover.

cell biology↗

bioRxiv2025

Novel function of Contactin associated protein 1 (Caspr 1)/ Paranodin in embryonic cortical neurons: hypoxia modulated neurite development.

Hypoxia, a condition of inadequate oxygen supply, is a common phenomenon affecting neurons and brain tissue, leading to significant implications for neuronal health and function. The prevalence of hypoxia in the brain is associated with various neurological conditions, making it a critical area of study. Neuritogenesis, the process of neurite outgrowth, is an essential aspect of neuronal development and connectivity and is particularly sensitive to hypoxic stress. Investigating how hypoxia affects neurite outgrowth is vital for understanding neuronal response and adaptation under low oxygen conditions. This study explores how hypoxic stress affects neurite regulation mediated by Contactin Associated Protein-1 (Caspr1) in primary mouse embryonic cortical neurons. Hypoxia, induced by culturing neurons in a 2% oxygen environment, significantly reduced neurite length and induced notable changes in growth cone morphology. Concurrently, we observed an upregulation in the expression of Caspr1 and its transcriptional regulator C/EBP, suggesting a compensatory role for Caspr1 in neurite extension under low oxygen conditions. Shorter hypoxia exposure periods revealed a dynamic biphasic response in Caspr1 levels, with an initial decrease followed by a substantial increase, correlating with corresponding changes in neurite length. This pattern emphasizes the critical involvement of Caspr1 in adapting neurite growth to fluctuating hypoxia duration. Furthermore, comparative analyses using wild-type and Caspr1 knockout Neuro2a cells demonstrated that the absence of Caspr1 mitigates hypoxia-induced neurite shortening, indicating a potential protective role against hypoxic stress. Additionally, hypoxia profoundly impacted mitochondrial morphology and function. Under hypoxic conditions, mitochondria transitioned to a more spherical shape. Mitochondrial respiration analysis revealed significant reductions in oxygen consumption rates (OCR), highlighting compromised mitochondrial function during hypoxia. These findings underscore the multifaceted role of Caspr1 in neurite regulation and mitochondrial adaptation to hypoxic stress. The study provides insights into the molecular mechanisms underpinning hypoxia-induced changes in neuronal morphology and function. Understanding these processes opens avenues for therapeutic strategies targeting Caspr1 in treating neurological disorders characterized by hypoxic stress. Future research will benefit from extending these investigations to more complex models, such as brain organoids, to further elucidate the metabolic and structural changes under hypoxia and their implications for neurodegenerative diseases.

neuroscience↗