A NEW study has uncovered a key molecular pathway that helps explain why nerve regeneration is impaired in diabetes, and importantly, how this barrier to repair might be reversed. The findings provide compelling evidence for a targetable mechanism that could improve recovery after nerve injury in people with diabetes, a population at heightened risk of neuropathy and poor healing outcomes.
p35–CDK5 Activity Identified as Central Block to Nerve Regeneration
Using mouse models of both type 1 and type 2 diabetes, researchers found that sensory neurons from diabetic animals showed markedly increased levels of the regulatory protein p35. Elevated p35 led to hyperactivation of cyclin-dependent kinase 5 (CDK5), which in turn triggered inhibitory phosphorylation of collapsin response mediator protein 2 (CRMP2), a key promoter of axon growth and regeneration.
Crucially, these molecular changes occurred before the onset of clinically detectable diabetic neuropathy, suggesting that disrupted repair capacity is an early and intrinsic consequence of diabetes rather than a late-stage complication.
Restoring Axon Growth by Targeting the Pathway
The research team tested multiple strategies to interrupt this pathway, including blocking the interaction between p35 and CDK5, reducing p35 expression, and preventing CRMP2 inhibition. All interventions successfully restored axon regeneration in diabetic neurons. Importantly, these approaches did not alter nerve repair in nondiabetic mice, indicating a diabetes-specific therapeutic window.
Systemic administration of a peptide designed to inhibit p35-CDK5 activity also improved motor and sensory recovery in long-term diabetic mice with established neuropathy, demonstrating relevance even in chronic disease.
Implications for Improving Nerve Function in Diabetes
These results identify the p35-CDK5-CRMP2 axis, and associated GSK3β signalling, as central drivers of impaired nerve regeneration in diabetes. By reversing these signalling changes, researchers were able to restore nerve repair in multiple diabetic models.
For clinicians, the study highlights a promising new therapeutic direction that could eventually improve outcomes after nerve injury and potentially mitigate progression of diabetic neuropathy.
Reference
Gobrecht P et al. Failure of nerve regeneration in mouse models of diabetes is caused by p35-mediated CDK5 hyperactivity. Sci Transl Med. 2025;17(826):eadp5849.
