1800 244 735

Helpline (02) 9874 9777

Are there genetic connections between neurodegenerative diseases?

A group of researchers working on ALS (Lou Gehrig’s disease) in yeast cells have found an unexpected genetic link between ALS and SCA-2, a disease in the same genetic family as HD. New links between these diseases might reveal new ways of approaching the search for treatments for diseases like HD.

What are polyQ diseases?

HD is one of a family of disorders caused by similar mutations in patients' DNA. DNA is like a recipe written with a very simple alphabet of four letters – A, C, G and T. In DNA, these letters are called ‘bases’.

The mutation that causes HD is an abnormally long sequence of C-A-G in the DNA that’s the recipe for the huntingtin protein.

Proteins are the molecules that do the work of the cell. They start out a bit like DNA – as long strings of repeating chemicals that we represent as letters. Proteins use a larger alphabet though – 22 letters. One of the protein ‘letters’ is glutamine, which we abbreviate as Q. The expanded CAG sequence in the HD gene results in a huntingtin protein with too many glutamines at the start of it. Because HD is caused by an increased number of glutamines, scientists call it a polyglutamine, or polyQ, disease.

In all, there are nine polyQ diseases, each caused by a CAG expansion in a different gene. They all result in the death of neurons, but the cells that die are somewhat different in each case. This unique pattern of brain cell death causes different symptoms in each disease.

Six of the nine diseases are called spinocerebellar ataxias, because the neurons that die are in a region of the brain called the cerebellum and the spinal cord. These diseases cause problems in coordinating movement, or ‘ataxia’ – hence ‘spinocerebellar ataxia’.

The more common neurodegenerative diseases, like Alzheimer’s, Parkinson’s and ALS (Lou Gehrig’s disease) are not usually caused by a single mutation. We usually can’t tell why a person gets one of these diseases – some unknown combination of genetic and environmental factors leads to the disease. Understanding what these factors are, might lead to treatments for these diseases, or at least improved understanding of why they occur.

A connection between SCA2 and ALS?

A group of scientists led by Aaron Gitler at the University of Pennsylvania set out to discover what genetic factors influence the death of cells in ALS. They used yeast cells to model the disease, which allowed them to look at over 5,000 genes to map out which ones caused more or fewer cells to die. Surprisingly, they discovered that a gene called ataxin-2 harmed the yeast model of ALS, by directly interacting with an ALS-related protein called TDP-43.

What has this to do with HD? Well, the ataxin-2 gene can develop an expanded CAG repeat, and when it does, it causes a polyQ disease called spinocerebellar ataxia type 2 (SCA2). This suggests there may be a connection between ALS and ataxin-2 – a gene that can cause polyQ diseases. That sort of connection has never been made before and it might be relevant to HD research.

Some additional experiments in cells confirmed their hunch about the physical interaction between the TDP-43 and SCA2 proteins, but the scientists wondered whether their discovery is applicable to humans, considering they discovered it in yeast cells. How could they test this?

Intermediate alleles

In HD, the length of a person’s CAG expansion is a major factor in the age of disease onset. More than 36 CAG repeats in the huntingtin gene will always lead to HD symptoms, if a person lives long enough, and longer CAG repeats tend to produce an earlier age of onset.

Some patients have repeats between 27 and 35 CAGs. These are called intermediate alleles, meaning they won’t cause symptoms, but are higher than the norm, which is about 17 CAGs.

In SCA2, there is a similar relationship between CAG repeat length in the ataxin-2 gene and the age of onset of symptoms. Most people have a CAG repeat length of about 22 in their ataxin-2 gene, while SCA2 patients have a repeat of greater than 34. CAG repeats between 24 and 34 in the ataxin-2 gene are considered ‘intermediate’.

The researchers looked at whether longer CAG repeats in ataxin-2 made the yeast ALS cells worse, and found that they did. Next, they did a very clever experiment, which was to measure the length of the CAG repeat length in the ataxin-2 gene in human patients with ALS. None of these patients had the sorts of symptoms caused by SCA2, but the researchers wondered whether the link between the CAG length of their ataxin-2 gene and ALS was present in humans, too.

They found that intermediate CAG repeat lengths in ataxin-2 were much more likely than expected in patients with ALS. This suggests that longer CAG repeats in ataxin-2 are a powerful risk factor for ALS. We don’t understand the details of this link, but it suggests there are connections between these diseases that we didn’t appreciate before.

Why do we care?

The authors don’t believe that this same connection exists between the CAG repeat length in the HD gene and ALS. But what they have shown is that unexpected connections might exist between the neurodegenerative diseases, and that studying something as simple as yeast can reveal unexpected features of these diseases. These connections give scientists new targets to explore in trying to understand what causes these devastating conditions. Finding these links between these diseases also gives us hope that therapies discovered for one might help others.

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

Latest Research Articles

Treatment for neurological disorder could be repurposed for Huntington’s disease patients

Published date: 22 October, 2020

While developing a drug called branaplam for patients with SMA, the pharmaceutical company Novartis discovered that it could hold promise for people with HD. The FDA has granted a special status called Orphan Drug Designation to branaplam. An existing drug…for huntingtin lowering? The pharmaceutical company Novartis has announced that the U.S. Food and Drug Administration ... Read more Treatment for neurological disorder could be repurposed for Huntington’s disease patients

Updates from the EHDN Plenary Meeting 2020

Published date: 9 October, 2020

In September, the European Huntington’s Disease Network (EHDN) hosted a virtual webinar event which comprised presentations on some of the latest scientific research as well as clinical studies of Huntington’s disease (HD). Researchers, doctors, patients and other interested folks, tuned in for an afternoon of talks as well as question and answer sessions to learn ... Read more Updates from the EHDN Plenary Meeting 2020

Sad news from the SIGNAL study: pepinemab does not influence HD symptoms

Published date: 23 September, 2020

The SIGNAL clinical trial was designed to test a drug called pepinemab in people with early Huntington’s disease. The key results of that trial were recently announced, and unfortunately, pepinemab did not slow or improve HD symptoms as hoped. What was the SIGNAL trial, and who participated? The SIGNAL trial was launched in 2015 by ... Read more Sad news from the SIGNAL study: pepinemab does not influence HD symptoms

When genes are unstable: targeting somatic instability in HD

Published date: 8 September, 2020

What is somatic instability? We tend to think of DNA as a fixed blueprint, an overarching plan for the biological bricks and bridges that constitute our cells, organs, and bodies. But like any good plan, DNA is actually dynamic and adaptable. It gets frequent use as a template for creating the RNA messages that pave ... Read more When genes are unstable: targeting somatic instability in HD

Working as a team: Changes in brain development mean some brain regions may be slacking off

Published date: 17 August, 2020

The effect of the HD genetic expansion on brain development has been a hot topic in HD research. A team of researchers led by Dr. Sandrine Humbert at the Grenoble Institut Neurosciences, examined human fetal tissue to show that the mutant HD gene causes very early changes in the patterns of early brain development. But ... Read more Working as a team: Changes in brain development mean some brain regions may be slacking off

Caution urged for the use of gene-editing technology CRISPR

Published date: 12 August, 2020

A gene-editing tool known as CRISPR has been heralded as a breakthrough technology for scientists in the lab but also as a potential strategy to treat numerous genetic diseases, including Huntington’s. But a series of recent studies has suggested that CRISPR is less precise than previously thought, leading to unintended changes in the genome. Three ... Read more Caution urged for the use of gene-editing technology CRISPR

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.