​Looking for the smoking gun behind sporadic MND

It has been three years since the ALS/MND Ice Bucket Challenge swept the world to raise awareness of motor neurone disease (MND) and funds for research. More than 2.4 million tagged videos circulated on Facebook featuring an assortment of people gasping in the wake of a bucket of ice and water dumped over their heads.
From the rich and famous to the everyday follower, more than 17 million people took on the challenge unable to resist the campaign’s quirky mix of competitiveness and fun. Critics described the campaign as a narcissistic fad. Yet the reality is the actions of the ice-bucketeers have had far-reaching consequences, raising awareness as well as over US$220 million worldwide for ALS/MND research and care, accelerating the pace of discovery for more effective treatments.

In Australia, over $3 million was donated to support MND research and care. Donations from 30,000 Australians funded a $1.05 million MND Australia Ice Bucket Challenge Grant awarded by the MND Research Institute of Australia (MNDRIA) to Professor Naomi Wray based at the University of Queensland and Associate Professor Ian Blair from Macquarie University in 2015. Their mission, to understand the genetic causes of sporadic MND. Ninety per cent of MND cases are sporadic. For the vast majority of people with MND, their diagnosis comes out of the blue with no known family history. Sporadic MND is a complex disease (like immune disorders, heart disease and diabetes) influenced by many genetic and environmental risk factors.

Professor Naomi Wray  Associate Professor Ian BlairAnjali Henders

MNDRIA funding has enabled Professors Wray and Blair to set up a consortium that brings together sixteen researchers from nine MND centres across Australia. Known as the SALSA-SGC (the Sporadic ALS Australian Systems Genomics Consortium), the group has built an integrated infrastructure to collect and analyse samples from Australians with sporadic MND. The program is undoubtedly ambitious and not for the faint hearted; coordinating nine centres to form a consortium is no easy task. Project Manager Anjali Henders drives SALSA at the coalface. At the outset, she coordinated meetings to help researchers at different centres agree on the types of information they should collect. Meanwhile, training sessions involving all sites ensured protocols for collection and handling of samples were the same across Australia. Researchers at each site were also provided with the necessary ethics documents to facilitate their Human Research Ethics Committee submissions to allow them to collect and analyse samples. The team has recently completed the design and build of a secure online database for managing the collection of demographic and clinical data, and tracking biological samples collected. 

The bid to better understand the genes involved in sporadic MND is now well underway. The SALSA team are looking for variations in genes known as mutations and also single nucleotide polymorphisms (SNPs) to see if they are associated with disease. Another key research angle involves investigating methylation of genes. Methylation or the addition of a methyl group to DNA occurs normally to regulate gene activity. However, over a lifetime DNA methylation can change, perhaps in response to environmental exposures. These changes can switch off genes inappropriately, leading to disease. By comparing the DNA of those with MND to those without MND, researchers can identify multiple new genes that play a role in sporadic MND. Because everyone carries some genetic risk factors for MND, thousands of blood samples are needed to be able to draw solid conclusions. SALSA feeds into a global effort to find genes underlying sporadic MND known as Project MinE, which has 17 countries on board.
Ice Bucket Challenge legacy infographic
In the past year, SALSA has recruited and collected data from 136 people with MND across Australia, at multiple time points. The Consortium has also conducted SNP analysis on 400 individuals, which includes samples collected from QLD, NSW, WA and VIC. The data are now being analysed as part of a much bigger MND study of 1700 people. Importantly, Professors Wray and Blair were able to leverage MNDRIA funding to win additional support from the National Health and Medical Research Council for this larger study.

Further research is now looking at DNA methylation and sequencing the complete genetic make-up (whole genome) of people with MND. Methylation typing of 1200 samples began in June 2017. Whole genome sequencing and analysis of samples from 110 people is also underway. These samples will then be shared with the international effort, Project MinE. In addition, a questionnaire to investigate genetic and environmental risk factors will also help to understand sporadic MND. Participants will be invited through their local SALSA clinic to complete the 40-minute online questionnaire via a secure web-link. Funded by the UK Halpin Trust, this initiative is another example of MNDRIA’s funding leading to support from other sources.

The Ice Bucket Challenge has left an enduring legacy to Australia. Thanks to the community’s generosity, a framework to understand the genetic basis of sporadic MND has been established and paves the way to ultimately find new treatments for MND. SALSA’s research is designed to ensure information about differences between people is fed back into other lines of investigation, so that research uses all clues that can be provided from people with sporadic MND as well as familial MND. Biobanking through SALSA will provide a resource for researchers with different interests for many years.

Australian samples contributed to the follow-up confirmation part of a major study published in the prestigious journal Nature Genetics in 2016 that found a new gene, C21orf2, is associated with risk of developing MND, as well as implicating several other potential genes. SALSA is now geared up to fully contribute to the next international study. As sample sizes get bigger globally, the SALSA team are confident more genes associated with MND will be found. Over the last five years, genetics studies in other complex diseases have been illuminating and their results have been meshed with a wide range of knowledge sometimes leading to drug repurposing or a whole new angle of research not previously considered. The researchers hope the same will be true for MND.

People with MND interested in participating in SALSA should talk to their neurologist. Anyone with a MND diagnosis not enrolled in research at the major MND clinics and who would like to donate a blood sample for this research should email Anjali Henders.
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