Convergence and Crosstalk of Stress Signaling Controlling Neuronal Survival
Despite the many different types of insults neurons may face, from physical damage to toxins to disease, there are only a few primary cellular signaling pathways stimulated by these divergent stresses. Supported by funds from NINDS, the Watkins Lab is uncovering how two prominent stress pathways are coordinately initiated by axon injury and the mechanisms by which these two arms of the response collaborate to promote the deaths of neurons in the CNS. Understanding how the convergence of multiple mechanisms results in neuronal loss may offer opportunities for neuroprotective interventions.
Mechanisms of the Pro-Regenerative Response to Axon Injury
The two arms of the axon injury response not only regulate neuronal survival but also a potent transcriptional program that can support axon regeneration. With support from NINDS, the Watkins Lab aims to understand how each arm contributes to this program to guide efforts to improve recovery after peripheral nerve injury and stimulate CNS repair.
Understanding the Contributions of Various Aspects of the Axon Injury Response
The transcriptional program that regulates neuronal survival and axon regenerative potential after injury is remarkably broad, involving thousands of changes in gene expression. Work from many laboratories over the last two decades has uncovered the contributions of a few dozen of these to neuronal death, axon regeneration, or axon degeneration. Supported by funds from the TIRR Foundation’s Mission Connect and the Glaucoma Research Foundation, the Watkins Lab is working to establish a new approach to allow for assessment of dozens of these potential targets at once across all three phenotypes of interest: neuronal death, axon regeneration, and axon degeneration. This approach may also all for more rapid evaluation of combinatorial interventions that are likely to be essential for overcoming the multiple barriers to axon regeneration in spinal cord injury and other conditions affecting CNS axons, such as glaucoma.
Controlled Stimulation of Neuronal Stress Signaling to Promote CNS Repair
Though most peripheral nerve injuries robustly engage the neuronal stress signaling that stimulates the intrinsic program for axon regeneration, the response in the CNS depends strongly on the type and location of injury. The failure to activate a sustained regenerative program can limit regenerative potential even when other potent barriers to CNS axon repair are relieved. In a project supported by the BrightFocus Foundation, the Watkins Lab has engineered drug-activatable neuronal stress signaling to determine which patterns of stimulated activity can improve regenerative potential without triggering neurodegeneration. This effort aims to capitalize on the intrinsic programs for the recovery after peripheral injury to facilitate the success of regenerative interventions in the CNS.
Could Neurodegeneration Sometimes be Beneficial?
Preserving irreplaceable neurons is understandably a central goal of neurodegeneration research. Diseased neurons, however, may in some cases be responsible for spreading their pathology to connected neurons, resulting in its progressive spread through multiple brain regions. In a collaborative pilot study with the laboratory of David Simon (Weill Cornell) supported by the Chan-Zuckerberg Initiative, the Watkins Lab is exploring whether the potential roles of early neuronal death in controlling the rate and extent of neurodegenerative disease progression. This study involves the development of new models for detecting and modulating the spread of protein species thought to be important mediators of transmission of disease across brain regions.
