PI 3‐kinase delta enhances axonal PIP 3 to support axon regeneration in the adult CNS
This study focuses on regeneration in the injured optic nerve, as part of projects aimed at repairing the damage that can occur in the optic nerve due to degenerative conditions such as glaucoma. It is also part of major research projects aimed at stimulating axon regeneration in the injured spinal cord. Spinal Research is proud to have supported this vital work alongside a number of key international bodies.
Below we briefly explain the paper, but to read it in full please follow this link.
Problem
Young neurons in the central nervous system (CNS) can regrow their axons after injury, but this ability is lost as they mature. Axonal injury or disease in the adult brain, eyes and spinal cord therefore has devastating consequences, and can result in neurological impairment, vision loss or paralysis. Conversely, neurons of the peripheral nervous system (PNS) maintain the ability to regenerate their axons into adulthood. Comparing PNS and CNS neurons is one approach to identifying new ways of promoting injured CNS axons to regenerate after injury.
Results
Our study found that adult PNS neurons use two versions of the enzyme PI 3‐kinase to regenerate their axons, p110δ and p110α. These enzymes generate the phospholipid PIP3. Visualisation of PIP3 in maturing CNS neurons revealed that PIP3 is strongly downregulated at the time when these neurons lose their regenerative ability. Overexpression of p110δ elevated axonal PIP3 and regeneration after laser injury, but p110α required the activating H1047R mutation to behave similarly, demonstrating that native p110δ functions in a hyperactive fashion. The study found that p110δ functioned through multiple mechanisms, including the enhanced transport of regenerative machinery into axons. Importantly, viral delivery of p110δ to the retina promoted axon regeneration after an optic nerve crush injury and was accompanied by enhanced survival of RGC neurons in the retina.
Impact
These findings suggest that signalling through PI 3‐kinase‐linked receptors is limited in adult CNS axons, contributing to their weak regenerative ability. Exogenous expression of the p110δ subunit elevates axonal PI 3‐kinase activity by functioning in a hyperactive fashion, leading to enhanced regeneration in human and rodent models of CNS injury, and enhanced neuroprotection and regeneration after a mouse optic nerve crush injury