Huntington’s Treatment May Come from Fix of Broken DNA Repair Mechanism

There is no treatment currently available to alter the course of Huntington’s disease (HD,) a hereditary neurodegenerative illness that results in uncontrolled movements, emotional problems and loss of cognition.

A Canadian group of researchers is working to change that, with a new theory about the cause of HD that may lead to a potential path for a treatment.

Their latest paper, entitled “N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation” was published in the Proceedings of the National Academy of Sciences of the United States of America.

HD is caused by mutations in the HTT gene that encodes the huntingtin protein. The first 17 amino acids of huntingtin comprise an amphipathic alpha-helical domain that can target huntingtn to the endoplasmic reticulum (ER). Although this region, N17, is typically phosphorylated at two serines, its hypophosphorylated state in HD is known to be important for disease development in mouse models.

In this current study, the researchers sought to identify compounds that could restore N17 phosphorylation. One compound identified from this screen was N6-furfuryladenine (N6FFA), also known as “kinetin.”

When tested, N6FFA increased phosphorylation of N17 in cells expressing mutant Huntingtin. It also reduced cortical mutant huntingtin inclusions and corrected phenotypes in an HD mouse model.

“Based on dosing by different ways of this molecule in mouse Huntington’s disease models, Huntington’s disease symptoms were reversed,” says first author Laura Bowie, Ph.D. candidate, department of biochemistry and biomedical sciences at McMaster University.  “The mutant huntingtin protein levels were also restored to normal, which was a surprise to us.”

The researchers propose the mechanism that N6FFA uses to restore phosphorylation.

They write that “N6FFA has been broadly categorized as an antioxidant; however, we note that N6FFA increases huntingtin phosphorylation, whereas antioxidants decrease phosphorylation. More recent studies have shown that N6FFA is not effective in scavenging free radicals but instead activates other antioxidant defense mechanisms. Our results support an alternative mechanism in which huntingtin is directly modified by N6FFA.”

Their results indicate that the increase in N17 phosphorylation upon N6FFA treatment occurs through its conversion to KTP by nucleotide salvaging.

Their proposed model is that N6FFA provides a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, yielding protective effects in HD model systems.

This nucleotide salvaging is important when neurons are stressed and have very low or absent energy levels, as in the context of HD. The authors propose that N6FFA is a type of signaling from DNA-damage repair that occurs at dangerously low ATP levels.

Regarding this idea, Dr. Bowie says, “The concept was that if we applied the signaling molecule back in excess, even orally, this signaling can be restored in the Huntington’s disease mouse brain.” She adds, “The net result was that we fixed the modification of huntingtin not seen in mutant huntingtin in Huntington’s disease.”

The senior author on the study, Ray Truant Ph.D., professor, biochemistry and biomedical sciences at McMaster University, cites the findings in this paper as some of the most important during his career. He states that “this is an important new lead and a new hypothesis, but it is important for people to know this is not a drug or cure.”

Dr. Truant suggests that the amyloid/protein misfolding hypothesis is likely the result of the disease, rather than its cause and that “this is the first new hypothesis for Huntington’s disease in 25 years that does not rely on the version of the amyloid hypothesis which has consistently failed in drug development for other diseases.”

The idea that there is a unique type of signaling coming from damaged DNA that signals huntingtin activity in DNA repair, and that this signaling is defective in Huntington’s disease may shift the course of HD research and treatments development.

Reference

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