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bioRxiv · 10.64898/2026.01.03.691327

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

Devanathan, V.·Sharma, S.·Shree, S.·Suresh, G.·Chakravarthy, H.·Schmelz, M.·Bali, K. K.·Dugar, S.·Sahu, B. S.·Kaur, I.
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Abstract

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.

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Devanathan, V., Sharma, S., Shree, S., Suresh, G., Chakravarthy, H., Schmelz, M., Bali, K. K., Dugar, S., Sahu, B. S., Kaur, I.. 2026-01-03. Hyperglycemia transcriptionally regulates the paranodal protein (Caspr1) in retinal neurons and modulates neurite extension. https://doi.org/10.64898/2026.01.03.691327

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