Blocking a diabetes-activated p35-CDK5 pathway restores nerve regeneration

Aims: To investigate how the inhibition of collagen response mediator protein 2 (CRMP2), a substrate of glycogen synthase kinase 3 (GSK3) that plays a role in axon regeneration, contributes to axonal damage in type 1 and type 2 diabetes. 

Methods: Mouse models of type 1 (streptozotocin, STZ) and type 2 diabetes (db/db) compared with control mice were investigated to assess nerve conduction velocity, compound muscle action potentials, and intraepidermal nerve fiber density in the footpads at 3 and 6 months. Half of animals underwent sciatic nerve crush 3 days before tissue isolation to inactivate GSK3. Western blotting and immunohistochemistry in neurons were used to analyze GSK3 isoforms. Interventions consisted of constitutively active CRMP2 expression, p35 knockdown, cyclin-dependent kinase 5 (CDK5) inhibition by CDK5 inhibitory peptide (CIP), GSK3β knockout, and a systemically administered anti-p35/CDK5 peptide.

Results: Diabetic neurons displayed increased p35 expression, leading to CDK5 hyperactivation and inhibitory phosphorylation of CRMP2, which impaired nerve regeneration and delayed behavioral recovery even before the onset of diabetic neuropathy. In control neurons, p35 overexpression compromised axon growth, while p35 knockdown restored impaired regeneration in diabetic neurons. Axonal regenerative capacity was restored by CIP. Systemic administration of the anti-p35/CDK5 peptide reduced CRMP2 phosphorylation in neurons and accelerated functional recovery in STZ mice.

Conclusions: An up-regulation of neuronal p35 expression and elevated CDK5 activity, leading to the inactivation of axonal CRMP2, may represent an important mechanism contributing to impaired axon regeneration in diabetes. This signaling axis may provide a novel therapeutic target to improve nerve regeneration.

Comments: This comprehensive experimental study addresses impaired axonal regeneration due to diabetes using a wide range of sophisticated techniques, and provides a compelling intervention strategy to restore regenerative capacity in order to prevent or treat diabetic nerve damage. However, the number of animals per group was small (in some experiments n=3 to 4), which limits statistical robustness. Some effects were observed only in one of the two diabetes models, indicating that differential mechanisms of impaired nerve regeneration in type 1 versus type 2 diabetes warrant further investigation. Demonstrating comparable effects in human neuronal models would strengthen the translational relevance of these findings for diabetic neuropathy in humans.

Gidon J Bönhof

Reference. Gobrecht P, Gebel J, Gisselmann G, Haastert-Talini K, Fischer D. Failure of nerve regeneration in mouse models of diabetes is caused by p35-mediated CDK5 hyperactivity. Sci Transl Med. 2025 Nov 26;17(826):eadp5849. doi: 10.1126/scitranslmed.adp5849. Epub 2025 Nov 26. PMID: 41296830.

🔗 https://www.science.org/doi/10.1126/scitranslmed.adp5849?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed