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Solving the Parkinson’s Puzzle: Identification of expanded and interrupted ATXN2 repeat expansions
Friday, 30th January 2026
Over 200,000 Australians are currently living with Parkinson’s disease, with a further 38 diagnosed everyday. It’s the fastest growing neurological disorder in the world, and there is still no cure. In our ‘Solving the Parkinson’s Puzzle’ series, we are speaking to leading Australian researchers to find out how their work is helping to slow, stop and ultimately cure Parkinson’s disease.
In our last chat with Professor Melanie Bahlo AM, we heard about her research into the role of repeat expansions and mitochondrial dysfunction in Parkinson’s disease. Dr. Bahlo’s research team have developed novel computational tools that enable them to discover genetic signals of PD in a person’s DNA.
This work is vital in expanding our understanding of Parkinson’s disease. A little more than 20 years ago, scientists thought there was no genetic connection to Parkinson’s at all. Today, The Michael J. Fox Foundation notes that scientists have linked about 10 percent of Parkinson’s cases to a direct genetic cause. In addition, research has discovered changes in other genetic locations that appear to influence the risk of getting Parkinson’s. We know there is still a lot to uncover about the genetic influence on Parkinson’s disease, which can help lead us to new treatments and faster results.
With research recently published in npj Parkinson’s Disease, we heard from Dr Bahlo, Dr Haloom Rafehi and Dr Fei Wang from WEHI about their research into the role of a specific type of genetic variation.
Can you tell us briefly what this research involved?
We investigated the role of a type of genetic variation – known as a ‘repeat expansion’ – as a potential rare cause of Parkinson’s Disease (PD) and Lewy Body Dementia (LBD). This interesting type of genetic variation is known to cause about 50 human diseases, including several movement disorders that resemble PD. Many repeat expansions are much rarer than PD, and may be misdiagnosed as Parkinson’s. We set out to see if known disease-causing repeat expansions are seen more frequently in people living with PD, compared to the general population.
Are you able to explain further what a ‘repeat expansion’ is?
DNA is made up of multiple chains of four types of amino acids, labelled “A”, “G”, “C” and “T”. A complete set of human DNA, referred to as a genome, contains approximately 3 billion amino acids. Sometimes there are bits of this long chain where a short ‘motif’ of between one to six of any of the A, G, C and Ts is repeated.
An example is the three-base motif “CAG”. In individuals with no disease, the number of times the CAG is repeated can vary but lies below a threshold. If the number of copies exceeds this threshold it can cause a disease called a repeat expansion disorder. Several diseases, including Huntington’s Disease, also a movement disorder, are caused by longer tracts of repeated CAG motifs.
New computational methods developed in the last five years now allow researchers to assess the lengths of these repeat expansion disorders in people’s DNA, including those with Parkinson’s, using a read out of a person’s genome, called whole genome sequencing.
What do your research findings reveal about Parkinson’s disease and Lewy Body Dementia?
We found expanded ATXN2 repeats (>32 repeats) in 4 out of 2431 people with PD and 2 out of 2468 people with LBD, but found no-one with such an expansion in our control groups (2706 people). The gene ATXN2 has a known CAG repeat expansion which causes a movement disorder called spinocerebellar ataxia type 2 (SCA2). In recent years this repeat expansion has also been found in individuals with motor neuron disease, also a movement disorder. However, in the PD cohort we observed that most of the expanded ATXN2 repeats were “interrupted” with CAA repeats rather than perfectly pure CAG repeats.
We report for the first time that these expanded, interrupted ATXN2 repeats also appear in individuals with LBD. Overall, the burden of known repeat expansions in PD is quite small. It is not a major hidden genetic risk factor.
What is the impact of this finding?
Our work broadens our understanding of PD and LBD genetics. ATXN2 expansions are already known to cause other movement disorders. Finding them in PD and LBD supports the idea that some genetic factors can influence more than one brain condition.
What is unclear now is whether these findings indicate a phenomenon called pleiotropy, where the same genetic variant can cause multiple different diseases, or whether the (more common) PD diagnosis can also capture atypical SCA2. More work is needed to answer this question.
Repeat expansions can be missed as they require a different analysis pathway, not yet widely used. These results suggest that targeted genetic testing could be useful for a small subset of people, especially when symptoms overlap with other conditions, or the presentation is unusual.
What is the next stage of your research?
The next stage of this research project will involve looking for novel repeat expansions in PD and LBD, i.e. moving beyond the set of known repeat expansions that cause movement disorders. This is a computationally complex and expensive analysis which needs to be conducted in a safe cloud environment, requiring different computational analysis methods.
