Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury

Matthew J. Taylor, Adam M. Thompson, Sharif Alhajlah, Richard I. Tuxworth, Zubair Ahmed

Research output: Contribution to journalArticlepeer-review

52 Downloads (Pure)

Abstract

DNA double-strand breaks occur in many acute and long-term neurological conditions, including neurodegeneration, neurotrauma, and stroke. Nonrepaired breaks chronically activate the DNA damage response in neurons, leading to neural dysfunction and apoptosis. Here, we show that targeting of the central ATM-Chk2 pathway regulating the response to double-strand breaks slows neural decline in Drosophila models of chronic neurodegeneration. Inhibitors of ATM-Chk2, but not the parallel ATR-Chk1 pathway, also promote marked, functional recovery after acute central nervous system injury in rats, suggesting that inhibiting nonhomologous end-joining rather than homologous recombination is crucial for neuroprotection. We demonstrate that the Chk2 inhibitor, prexasertib, which has been evaluated in phase 2 clinical trials for cancer, has potent neuroprotective effects and represents a new treatment option to promote functional recovery after spinal cord or optic nerve injury.
Original languageEnglish
Article numbereabq2611
JournalScience Advances
Volume8
Issue number37
DOIs
Publication statusPublished - 14 Sept 2022

Fingerprint

Dive into the research topics of 'Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury'. Together they form a unique fingerprint.

Cite this