Hexanucleotide repeats in the open reading frame 72 (C9orf72) of chromosome 9 is the most common kind of genetic inheritance associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These repeats result in the production of dipeptide repeat proteins, the most poisonous of which is called poly(PR). Researchers identified potential moderators of poly(PR) toxicity by conducting a kinome-wide CRISPR/Cas9 knock-out screen in human induced pluripotent stem cell (iPSC)-derived cortical neurons. They next verified the role of candidate modifiers by investigating their effects in vitro, in vivo, and ex vivo. The neuronal toxicity produced by polyamines could be averted by knocking down the NIMA-related kinase 6 (NEK6) poly (PR). Additionally, knocking down NEK6 improved the poly(PR)-induced axonopathy in zebrafish, and NEK6 was found to be abnormally expressed in C9orf72 patients. At least in part via repairing the DNA damage that was caused by p53, the suppression of NEK6 expression and the inhibition of NEK6 activity were able to rescue axonal transport abnormalities in cortical neurons that were derived from C9orf72 patient iPSCs. As a novel therapeutic target for C9orf72 FTD/ALS, we found NEK6, which modulates poly(PR)-mediated p53-related DNA damage. NEK6’s role in this process is to prevent DNA damage.
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