MYCOLab Ai Logo - gold and army green

Calcineurin-mediated regulation of growth-associated protein 43 is essential for neurite and synapse formation and protects against α-synuclein-induced degeneration

Summary

Researchers discovered that a specific protein called GAP-43 plays a crucial role in protecting brain cells from damage caused by α-synuclein, a protein involved in Parkinson’s Disease. When GAP-43 is modified through a process called phosphorylation at certain sites, it promotes the growth of neurites (neural connections) and formation of healthy synapses. The drug FK506, already approved by the FDA, appears to work by controlling this phosphorylation process, offering potential therapeutic benefits for Parkinson’s patients.

Background

Elevated calcium levels and hyperactivation of calcineurin contribute to α-synuclein pathobiology in Dementia with Lewy Bodies and Parkinson’s Disease. FK506, an FDA-approved calcineurin inhibitor, has been shown to provide neuroprotection against α-synuclein pathology, an effect associated with phosphorylation of growth-associated protein 43 (GAP-43).

Objective

To investigate the role of GAP-43 phosphorylation at calcineurin-sensitive sites in neurite morphology, synapse formation, and protection against α-synuclein-induced neurodegeneration using phosphomutant approaches.

Results

Phosphorylation at S86 and T172 of GAP-43 is crucial for neurite branching and synapse formation. Phosphomimetic GAP-43 mutants enhanced both processes and protected against α-synuclein-induced neurodegeneration. Phosphoablative mutants prevented these effects and showed increased interactions with ribosomal proteins.

Conclusion

Calcineurin-regulated phosphorylation of GAP-43 at S86 and T172 regulates neurite branching and synapse formation while protecting against α-synuclein toxicity. FK506’s neuroprotective effects may be partially mediated through GAP-43 phosphorylation, providing a potential therapeutic target for synucleinopathies.
  • Published in:Frontiers in Aging Neuroscience,
  • Study Type:Experimental Research,
  • Source: PMID: 40259946, DOI: 10.3389/fnagi.2025.1566465
Scroll to Top