Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration

Brain Communications, 2019 · DOI: 10.1093/braincomms/fcz005 · Published: July 2, 2019

Simple Explanation

DNA double-strand breaks are common in neurological disorders and can lead to neural dysfunction. The study found that reducing the DNA damage response is neuroprotective in models of neurodegeneration and promotes regeneration after neurotrauma. The researchers targeted the MRN complex, involved in DNA double-strand break recognition, and found it to be neuroprotective in Drosophila models and prevented synapse loss in hippocampal neurons. Attenuating the DNA damage response also promoted regeneration of retinal ganglion cells and dorsal root ganglion neurons, and restored function after spinal cord injury, suggesting potential therapies for nervous system repair.

Study Duration

Not specified

Participants

Drosophila models, rat primary hippocampal, DRG, and retinal cultures, adult Sprague-Dawley rats

Evidence Level

Not specified

Key Findings

1
Genetic targeting of the MRN complex is neuroprotective in Drosophila models of neurodegeneration, suppressing the decline in climbing ability and startle response in flies expressing Ab1-42, Htt.Q128, or Tau.
2
Inhibition of Mre11 or ATM prevents apoptosis and stimulates regeneration after neurotrauma, as demonstrated by increased RGC survival and neurite outgrowth in vitro and in vivo after optic nerve crush injury.
3
Mre11 and ATM inhibitors promote DRGN survival and neurite outgrowth in vitro and DC axon regeneration after SCI in vivo, leading to improved electrophysiological function and recovery of sensory and locomotor function.

Research Summary

The study demonstrates that attenuating the DNA damage response by targeting the MRN complex is neuroprotective in models of neurodegeneration, leading to improved outcomes in Drosophila models and mammalian neurons. Inhibition of Mre11 or ATM promotes significant RGC survival and axon regeneration after optic nerve crush injury, surpassing the effectiveness of existing treatments for RGC neuroprotection and axon regeneration. The use of Mre11 and ATM inhibitors or shRNA plasmids targeting Mre11 and ATM enhances DC axon regeneration and functional recovery after SCI, indicating a novel therapeutic strategy for neurological conditions.

Practical Implications

Therapeutic Potential

Targeting the DNA damage response presents a novel therapeutic strategy for treating neurological conditions, including neurodegenerative diseases and spinal cord injuries.

Clinical Translation

The use of intrathecal injection for administering Mre11 and ATM inhibitors in SCI can be directly translated to human therapy, offering a more efficient and targeted approach.

Drug Development

Repurposing chemotherapy agents like mirin and KU-60019, which are specific inhibitors of the DNA damage response, could provide effective treatments for SCI and other neurological disorders.

Study Limitations

1
Long-term targeting of the MRN complex could potentially cause cancer.
2
Inhibiting the DNA damage response may have negative consequences for cells and system functions if applied systemically.
3
Further studies are needed to investigate the long-term effects of DNA damage response inhibition and its impact on other cell types in the CNS, such as glia.

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