1800 244 735

Helpline (02) 9874 9777

Taking new targets to the bank: the DNA repair protein ‘ATM’ is overactive in Huntington's disease

A recent study by the Yang lab at UCLA points to a new idea for preventing damage to neurons in Huntington’s disease. The strategy is to tone down an overly helpful protein called ATM. Inside neurons, ATM provides a crucial role in repairing the cell’s infrastructure, somewhat like that of a bridge inspector, but the expanded HD protein may be causing ATM to misjudge DNA damage.

Nature’s inspectors, repair team, and demolition crew

ATM actually has nothing to do with a bank machine. ATM is an abbreviation for ‘Ataxia Telangiectasia Mutated’ because it is a gene that can cause a movement disorder called Ataxia Telangiectasia, but it may also play a role in Huntington’s disease.

The function of ATM in the cell is something like a building inspector. When bridges get old they often rust, and parts need to be replaced to keep roads safe. Most bridges are inspected at least once a year by intrepid engineers with climbing equipment who determine whether or not a bridge can be repaired, or will need to be condemned.

Inside our cells, DNA shows wear and tear with age too, developing cracks and even breaks in the structure. This DNA damage occurs as part of the normal aging process, but it is seen earlier than expected, or more often than expected, in Huntington’s disease patients. DNA damage is also seen in HD cell and animal models.

The job of the ATM protein is to detect this sort of DNA damage, and then hang around the damage site, calling in a team of specialized proteins to do the repairs. If the damage is too great, ATM activates a different set of proteins, a sort of demolition crew, which condemns and removes the cells harboring the damaged DNA. It is a tricky business—an overzealous inspector could actually condemn a structure prematurely, while an unobservant inspector might fail to detect and repair structural damage.

Making the right call

Actual bridge inspectors usually communicate with their teams via walkie-talkie. In cells, communication is done by fastening chemical tags known as phosphate groups to the right proteins. ATM calls in the repair team by ‘phosphorylating’ a protein called H2AX. H2AX then settles down at the site of the structural DNA break and gets the repair started. If the damage is too far-gone, ATM can phosphorylate a different protein, called p53, which brings in the demolition crew instead of the repair team. The demolition crew shuts down the entire cell in a process called apoptosis, or programmed cell death. Needless to say, a lot of problems can arise if the demolition crew is called in by mistake.

The work done in the Yang lab shows that ATM signaling is increased in Huntington’s disease, and this signaling may be going awry. When cells with the HD mutation were stressed, they showed more H2AX phosphorylation, and more cell death than expected. Excess H2AX phosphorylation was also found in brain tissue from HD patients, especially the portions of the brain that are known to be vulnerable in HD.

The question is whether extra ATM signaling in HD is a good thing, or a bad thing: in vulnerable brain regions, HD might cause more DNA damage, so ATM might be doing the right thing by signaling H2AX to make repairs. On the other hand, if overzealous ATM signaling is one of the detrimental effects caused by the expanded HD protein, then it could make a good target for a potential therapy.

Less is more

ATM is essential to normal health—patients with mutations in both copies of their ATM gene have a serious disorder called Ataxia Telangiectasia. Yet having only one functional copy of the ATM gene, a half dosage, doesn’t seem to cause any symptoms at all.

With this in mind, the Yang lab set out to study ATM signaling in several ways. They started by reducing the amount of ATM produced in HD cells grown in a dish, and found that blocking ATM signaling actually made the cells healthier. Somehow, ATM signaling may have been calling in the demolition team rather than the repair crew in the HD cells.

The research team then looked at fruit flies with the HD mutation, which have trouble with their coordination when climbing up test tubes. They generated HD flies with a half dose of ATM (only one copy of the fly ATM gene). These flies were much better climbers than the regular HD flies.

Finally, when the researchers bred ‘half dosage ATM’ mice with HD mice, they found the most convincing results of all—the HD mice appeared healthy! HD mice with reduced ATM moved better, showed fewer signs of depression, had fewer aggregates, and less brain atrophy than the HD mice with normal amounts of ATM. In other words, having half of the normal ATM prevented some of the problems caused by HD.

Taking the ATM target to the bank

It is possible to reduce the activity of ATM with a small molecule drug, called an inhibitor. The researchers put ATM inhibitors on neurons grown in a dish and they found that it protected the cells from damage done by the HD protein. This opens the possibility for the development of an ATM inhibitor medication to treat HD.

At this point, we don’t know how the HD protein causes abnormal ATM signaling. But two other studies have noticed the same thing, and this type of independent replication goes a long way to boost our confidence that we’re on the right track. Together, the results of these studies suggest that reducing ATM may be a promising new way to treat HD, and perhaps to prevent damage caused by the HD mutation.

Latest Research Articles

Roche Phase II GENERATION HD2 study underway

Published date: 14 February, 2023

Roche released a community letter last month, detailing how their Phase II clinical trial to study the huntingtin-lowering drug, tominersen, is now underway. Learn more about what this means in this article and at the recent HDSA Research Webinar, with representatives from the company. The ups and downs of huntingtin-lowering Tominersen is a type of ... Read more

Disappointing news from Novartis about branaplam and the VIBRANT-HD trial

Published date: 9 December, 2022

The pharmaceutical company Novartis has released a community update which announces that they are ending development of branaplam, a huntingtin lowering drug, for possible treatment in Huntington’s disease (HD). This news comes following recent bad news about side effects of branaplam in HD patients, being tested in the VIBRANT-HD clinical trial, dosing of which was ... Read more

Update on the PTC Therapeutics PIVOT-HD Trial

Published date: 2 November, 2022

Recruitment of participants into the US arm of the PTC Therapeutics PIVOT-HD trial has been paused. Since this announcement, there have been a lot of different (and confusing!) headlines about the pause in recruitment. In this article, we will lay out what is going on and what this announcement means. What is the aim of ... Read more

Forward momentum for Roche and Wave in latest news about huntingtin-lowering trials

Published date: 30 September, 2022

In the past week or so, during and following a big HD research conference, two companies developing medicines for Huntington’s disease announced news about their huntingtin-lowering drugs. First, the pharmaceutical company Roche announced plans for a new clinical trial of tominersen. Then, the genetic medicines company Wave Life Sciences shared early data showing that its ... Read more

Focusing in on fibrils; scientists give us a glimpse of huntingtin protein clumps

Published date: 8 September, 2022

A group of scientists from the EPFL in Lausanne, Switzerland have published a paper in the Journal of the American Chemical Society, describing clumps made up of a fragment of the huntingtin protein. A word that’s commonly used to describe these is “aggregates.” Using very powerful microscopes, the team was able to zoom in and ... Read more

Hereditary Disease Foundation (HDF) conference 2022 – Day 4

Published date: 2 September, 2022

DNA repair and CAG repeat instability The effect of HTT lowering on CAG repeat expansions Welcome to last day of the @hdfcures conference! We’ll only be sharing a few talks from today’s sessions, which focus on DNA repair. The first is from HDBuzz’s very own Jeff Carroll! Jeff will be sharing his work on HTT ... Read more