Huntington's disease therapeutics conference 2018 – day 2

Updates from day 2 of the Huntington’s Disease Therapeutics Conference focusing on DNA repair in HD.

Wednesday morning – DNA repair in HD

Good morning from the 2018 HD Therapeutics Conference! Today’s update is relatively brief because the afternoon was focused on poster presentations. The morning session focused on the role of DNA repair in HD – a hot topic these days, thanks to very interesting genetic studies of HD patients. These huge studies demonstrated that genetic variations, outside the HD gene, contribute to how soon HD symptoms occur in people carrying them. Surprisingly, many of these variations were in genes that help cells repair DNA.

Up first, Jong-Min Lee, Massachusetts General Hospital, updates the crowd on the latest results from the GeM-HD consortium – the international group of researchers searching genetic variations that influence HD onset. The GeM-HD consortium uses microchips that read tiny genetic variations across the entire genome of thousands of HD patients. This huge dataset lets them ask the question – are any of these variations influencing how early or late HD occurs? The latest version of the GeM-HD analysis includes 9,000 HD patients! This increase in sample size has enabled them to identify even more variations that modulate HD onset. These variations are strikingly close to even more DNA repair genes. Lee describes a very subtle variation in the sequence of the HD gene itself that also influences the age of HD symptom onset. The most dramatic effect GeM-HD has observed concern a gene called FAN1. Some variations in this gene have a beneficial effect on HD onset, and other variations have a bad effect. This suggests something FAN1 is doing is central to HD progression. Lee provides another stream of evidence which suggests that people who have more Fan1 in their brains have a later onset of HD. This shows the power of doing genetic studies – if we can find a way to bolster the activity of Fan1, it seems likely that it would be beneficial for HD progression.

Guo-Min Li, University of Texas Southwestern, studies a process called “mismatch repair”, one of the ways by which cells repair certain kinds of DNA damage. Mismatch repair allows cells to fix small errors that crop up when cells copy their DNA. Mutations in these genes lead to high rates of cancer, because genetic errors are left un-corrected. Li reminds the audience that while mismatch repair is normally very helpful for cells to remain healthy, it sometimes makes mistakes. One of these is the tendency for long repetitive stretches of DNA to lengthen. The mutation that causes every case of HD – a stretch of the DNA letters “C-A-G” – is one of these repetitive bits of DNA. Li’s lab is studying the process by which mismatch repair of long stretches of CAG makes them longer. Li’s lab has identified a few specific mismatch repair processes that drive CAG expansions – he suggests they may be a good target for new HD treatments.

Lorena Beese, Duke, also studies mismatch repair. Her lab focuses on the precise ways in which the mismatch repair proteins carry out their work – recognizing mistakes, cutting them out and then stitching the DNA back together. The machines that Beese’s lab has described in detail may be future targets for drugs designed to change how they interact with long CAG tracts, like the one in the HD gene.

Peter McKinnon, St. Jude Children’s Research Hospital, is an expert on DNA repair in the brain. He’s addressing the conference on the specific types of DNA damage that occur in the brain. The brain is interesting, from the point of view of DNA repair, because for most of our lives the neurons in our brain don’t divide. This means they can’t use some of the arms of the DNA repair pathways, which only work in dividing cells. McKinnon’s lab studies a specific kind of DNA damage called “base excision repair”, a process for fixing damage to only one of the two strands of DNA.

Partha Sarkar from University of Texas studies the Huntingtin protein and its direct interactions with DNA and DNA-handling proteins. Turns out mutant huntingtin hangs around with a protein called PNKP whose job is to look after DNA. In doing so, it prevents it doing its job. This raises the possibility that the HD mutation accelerates DNA damage.

Share on facebook
Share on twitter
Share on pinterest
Share on email

Latest Research Articles

HD and Histamines: Targeting Hybrid Receptors to Quiet Stressful Brain Talk

Published date: 15 July, 2020

Dopamine is an important chemical messenger in the brain that becomes imbalanced in Huntington’s disease. Researchers recently described a creative way to restore the balance and treat symptoms in HD mice, using an antihistamine drug that acts on hybrid dopamine receptors. It’s an innovative approach to HD therapeutics, but don’t start reaching for allergy meds ... Read more HD and Histamines: Targeting Hybrid Receptors to Quiet Stressful Brain Talk

Changing jobs: converting other cell types into neurons

Published date: 23 June, 2020

Researchers have known for quite some time that HD causes a progressive loss of neurons. But what if we could find a way to fill their place? In a new report, researchers used an intriguing strategy in living mice to do just that – they converted a different type of brain cell into neurons, with ... Read more Changing jobs: converting other cell types into neurons

HD Young Adult Study defines the sweet spot: symptom-free with measurable changes

Published date: 27 May, 2020

A new study headed up by Dr. Sarah Tabrizi, a pioneer in HD research, assessed pre-manifest HD young adults many years from predicted symptom onset with a battery of clinical tests. The goal of this study was to identify a sweet spot – a time when HD participants weren’t experiencing any observable symptoms, but when ... Read more HD Young Adult Study defines the sweet spot: symptom-free with measurable changes

Fountain of youth: HTT protein repairs neurons by maintaining youthful state

Published date: 13 May, 2020

A team of scientists has recently published their findings on how our bodies are able to repair brain and spinal cord injuries. They found that the huntingtin protein plays an important role in repairing damaged nerve cells. Repairing nervous system damage – the holy grail of medical science It has long been the ambition of ... Read more Fountain of youth: HTT protein repairs neurons by maintaining youthful state
Light and sleep

Light and Sleep

Published date: 7 April, 2020

Light & sleep Neurofilament Light Protein and Lifestyle Factors Commentary Words Dr Travis Cruickshank and Dr Danielle Bartlett

What does COVID-19 mean for Huntington’s disease families and HD research?

Published date: 6 April, 2020

COVID-19, short for coronavirus disease 2019, has taken the world by storm in almost every sense – many people have been infected with the SARS-CoV-2 virus, it’s created shopping pandemonium in stores, and many people are isolated at home. But behind that frenzied storm, scientists around the world have been working tirelessly to move research ... Read more What does COVID-19 mean for Huntington’s disease families and HD research?

Welcome to our new website!

Please bear with us while we iron out the last minute wrinkles! If you have any feedback about our new site, please fill out the form below.