27 September 2022
Genetic master switch could slow or reverse nerve cell damage
Published online 21 September 2022
Hacking cellular responses to DNA damage could provide new treatments for acute and long-term neurological conditions.
Researchers have identified a new way to prevent nervous system degeneration and trigger the re-growth of damaged nerve fibres. The discovery, so far only tested in animals, could lead to novel treatments for a wide range of neurological conditions, including Alzheimer’s disease and spinal cord injury.
Double-strand DNA breaks (DSBs) can be caused by normal cellular processes like metabolism, or exposure to external agents like the sun and X-rays. They are particularly dangerous in non-replicating cells like neurons, which cannot be readily replaced.
Organisms routinely fix DSBs, however they accumulate in neurological conditions. Failure to repair them can cause persistent activation of cellular DNA damage responses, leading to impaired nervous system functioning and apoptosis, or programmed cell death.
A team, led by Zubair Ahmed from the University of Birmingham, has shown that blocking expression of a gene that acts as a master regulator of responses to DSBs can prevent nerve cell death and help animals recover from central nervous system injury.
The researchers showed that blocking production of the protein checkpoint kinase-2 (Chk2), which is coded by the gene, reduced neurodegeneration in fruit flies and improved survival of cultured rat neurons.
In experiments designed to model spinal cord injury, rats treated with a Chk2-inhibiting drug rapidly regained sensory and movement skills, and exhibited significant axon, or nerve fibre, regeneration.
“We were astounded by their phenomenal recovery,” says Ahmed. “By four weeks after injury, the treated rats behaved as if they had not been injured, while untreated animals retained the deficits.”
The group, including Sharif Alhajlah, of Shaqra University, Saudi Arabia, achieved similar results in rats treated with prexasertib, a Chk2 inhibitor previously tested in a phase 2 trial as a cancer treatment.
Ahmed and colleagues are testing other potential Chk2 inhibitors as treatments for acute neurological conditions, including spinal cord, acoustic nerve and traumatic brain injuries, and chronic illnesses like Parkinson’s, Huntington’s and Alzheimer’s diseases.
They hope to speed the development of new drugs by repurposing compounds that have already been through early clinical trials.
“It’s interesting work that puts Chk2 on the map as a neuroprotective mechanism,” says neuroscientist Gabriel Balmus, of the University of Cambridge, UK. “Further work is, however, needed to better understand the mechanisms involved, and to find out whether this is just a symptomatic effect that prolongs the life of cells in the short-term or provides long-term solutions.”
Taylor, M. et al. Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury. Sci. Adv. 8,37 (2022).