Failure of nerve regeneration in mouse models of diabetes is caused by p35-mediated CDK5 hyperactivity
Philipp Gobrecht1, Jeannette Gebel1, Günter Gisselmann2
1Center for Pharmacology, Institute II, Medical Faculty and University of Cologne, 50937 Cologne, Germany.
Abstract:
Diabetes mellitus impairs axon regeneration, leading to chronic functional deficits after nerve injury. Here, we used a streptozotocin-induced model of type 1 diabetes and leptin receptor-deficient db/db mice representing type 2 diabetes to identify a key molecular mechanism underlying this failure and propose targeted strategies to restore regenerative capacity. As determined by Western blotting and immunohistochemistry, sensory neurons from diabetic mice displayed elevated p35 abundance, leading to cyclin-dependent kinase 5 (CDK5) hyperactivation and glycogen synthase kinase 3β (GSK3β)-dependent inhibitory phosphorylation of collapsin response mediator protein 2 (CRMP2), a critical regulator of axon growth. These changes, coinciding with impaired axon regeneration in injured sciatic nerves, occurred before the onset of diabetes-induced neuropathy in mice. Disrupting this pathway, through expression of constitutively active CRMP2, p35 knockdown, or blockade of the p35-CDK5 interaction by expression of the inhibitory protein CIP or injection of a TAT (transactivator of transcription) peptide, restored axon regeneration of cultured adult sensory neurons and accelerated motor and sensory recovery of diabetic mice. These manipulations did not affect nerve regeneration in nondiabetic mice. Similarly, GSK3β knockout prevented CRMP2 inactivation and rescued growth in diabetic neurons. Systemic administration of the peptide also enhanced motor and sensory nerve repair in long-term diabetic mice with established neuropathy. These findings identify p35 and CRMP2 as central effectors of diabetes-induced regenerative failure in mice, suggesting that the p35-CDK5-CRMP2 axis and GSK3β are promising therapeutic targets for promoting nerve repair in patients with diabetes.
Insights
Diabetes impairs nerve regeneration by altering p35, cyclin-dependent kinase 5 (CDK5), and collapsin response mediator protein 2 (CRMP2) pathways. Targeting these molecular mechanisms restored axon growth and nerve repair in diabetic mice.
Area of Science:
- Neuroscience
- Endocrinology
- Regenerative Medicine
Background:
- Diabetes mellitus is a major cause of impaired axon regeneration, leading to persistent functional deficits after nerve injury.
- The molecular mechanisms driving this regenerative failure in diabetes remain incompletely understood.
- Identifying these mechanisms is crucial for developing therapeutic strategies to restore nerve repair capacity.
Purpose of the Study:
- To identify key molecular mechanisms responsible for impaired axon regeneration in diabetes.
- To investigate the roles of p35, CDK5, GSK3β, and CRMP2 in diabetes-induced regenerative failure.
- To evaluate targeted strategies for restoring nerve regeneration in diabetic models.
Main Methods:
- Utilized streptozotocin-induced type 1 and leptin receptor-deficient db/db type 2 diabetes mouse models.
- Employed Western blotting and immunohistochemistry to analyze protein expression and phosphorylation.
- Intervened in the p35-CDK5-CRMP2 pathway using genetic and pharmacological approaches, including CRMP2 activation, p35 knockdown, p35-CDK5 interaction blockade, and GSK3β knockout.
Main Results:
- Diabetic sensory neurons exhibited elevated p35, leading to CDK5 hyperactivation and inhibitory GSK3β-dependent phosphorylation of CRMP2.
- These molecular changes preceded neuropathy onset and correlated with impaired sciatic nerve regeneration.
- Disrupting the p35-CDK5-CRMP2 axis or GSK3β activity restored axon regeneration in cultured diabetic neurons and accelerated functional recovery in vivo.
- Systemic peptide administration enhanced nerve repair even in long-term diabetic mice with neuropathy.
Conclusions:
- The p35-CDK5-CRMP2 signaling axis and GSK3β are identified as central mediators of diabetes-induced failure in axon regeneration.
- Targeting the p35-CDK5-CRMP2 pathway and GSK3β offers a promising therapeutic strategy for enhancing nerve repair in diabetic patients.
- These findings pave the way for novel treatments to address nerve damage associated with diabetes.
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