Research from the Collins lab is pointing to some places to look for future ideas on how to help patients recover from serious neuronal injuries, such as spinal cord injuries.
Axons -- long processes that enable neurons to communicate with one another-- are generally vulnerable to injury both because of their long length and also because once they are broken they are usually unable to grow again in the adult mammalian nervous system. Yet there are some exceptions, which include the peripheral nervous system (PNS), and younger animals. For neurons in the central nervous system (CNS) with a projection to the peripheral system, a second injury to the PNS projection can actually stimulate regeneration in the CNS. These exceptions are of great interest for understanding how axons in adult nervous system might be stimulated to regenerate.
Recent work in the Collins lab has uncovered an important aspect of the axon regeneration mechanism. Through work in both flies and mammalian neurons, the researchers found there is a convergence between a signaling molecule known to stimulate axonal regeneration, called cAMP, and signaling machinery within axons that becomes activated by axonal damage. The signal system acts as a 'damage sensor.'
A broadly known method to stimulate the growth potential of axons is to elevate intracellular levels of cAMP, however the cellular pathway(s) that mediate this are not known. The Collins group identifed the Dual Leucine-zipper Kinase (DLK, Wnd in Drosophila) as a critical target and effector of cAMP in injured axons. DLK/Wnd is thought to function as an injury 'sensor', as it becomes activated after axonal damage.
Writing in an eLife article published online, the authors report "Our findings in both Drosophila and mammalian neurons indicate that the cAMP effector kinase PKA is a conserved and direct upstream activator of Wnd/DLK. PKA is required for the induction of Wnd signaling in injured axons, and DLK is essential for the regenerative effects of cAMP in mammalian DRG neurons. These findings link two important mediators of responses to axonal injury, DLK/Wnd with cAMP/PKA, into a unified and evolutionarily conserved molecular pathway for stimulating the regenerative potential of injured axons."
An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK
Yan Hao, Erin Frey, Choya Yoon, Hetty Wong, Douglas Nestorovski, Lawrence B Holzman, Roman J Giger, Aaron DiAntonio, Catherine Collins