The following Grants were awarded on an annual basis by the Motor Neurone Disease Research Institute of Australia (MNDRIA)
| 2024 | Dr Luke McAlary University of Wollongong, NSW |
Deep mutational scanning to define and predict the pathogenicity of existing and future SOD1 mutations Mutations in the SOD1 gene cause MND. Every year, ~7 new SOD1 mutations are discovered in the population. Since the mutations are new, they are classified as “variants of uncertain significance”, which causes patient’s dismay due to delayed diagnosis and can sometimes prevent entry into clinical trials. Our team plans to systematically investigate every existing and possible mutation that can occur in the SOD1 gene to generate a database that will allow genetics counsellors and clinicians to effectively diagnose patients and more quickly begin offering care and support to them and their families. |
| 2023 | Dr Duncan Crombie University of Melbourne, VIC |
Utilising stem cells derived from people with MND to create artificial ‘mini-organs’ in the search for MND therapeutics Our research programs have identified measurable defects in some MND-specific stem cell-derived lower motor neurons. However, while very useful for drug screening, the way these neurons are grown are not representative of how they work in the human body. Utilising novel ‘neuromuscular organoid’ models, which contain functional motor neurons, skeletal muscle and other non-neuronal support cells, we will identify measurable differences between ‘sick’ and healthy organoids. This will confirm our findings on lower motor neurons and provide for a more complex cellular model of MND which can be used to support our research to identify new MND treatments. |
| 2022 | Professor Jacqueline Wilce Monash University, VIC |
Preventing toxic protein aggregation in cells by targeting stress granules This project investigates our newly developed TIA-1 inhibitor that has potential as a neuroprotective agent against ALS. In preliminary work we have tested the TIA-1 inhibitor in vitro and also shown that it is able to modulate stress granules (SG) in cells. SGs are subcellular structures made of protein and RNA that have been shown to trigger protein aggregation as underlies neurodegenerative disease. We anticipate that TIA-1 inhibitors will modulate SG formation, preventing the formation of neurotoxic aggregate formation. The work will provide proof-of-concept for targeting TIA-1 and potentially lead to a novel mode of intervention against ALS. |
| 2021 | Dr Nirma Perera Florey Institute of Neuroscience and Mental Health, VIC |
Autophagy in Neuroglia: a hidden player in abnormal MND proteostasis MND is characterised by accumulation of toxic protein deposits in motor neurons and surrounding neuronal supporting glial cells. Autophagy is the only pathway in our cells that can purge large protein deposits. Therapeutic rescue of autophagy to clear culprit protein aggregates may have therapeutic potential. Many studies so far have focused on exploring neuronal autophagy while glia autophagy remain unexplored. Using the powerful combination of an autophagy reporter mouse model, stem cell derived glia and post-mortem tissue, we will analyse autophagy in glia for the first time, providing new insights leading to therapeutic modulation of intricate autophagy pathway in MND. |
| 2020 | Dr Samantha Barton Florey Institute of Neuroscience and Mental Health, VIC |
Could abnormal myelin composition be exacerbating neuronal dysfunction in MND? Oligodendrocytes (a type of glial cell that forms myelin) have two key roles essential for motor neuron function: to myelinate (coat) neurons and to provide sources of energy to neurons. In MND, both functions are impaired but the contribution to neuronal dysfunction remains unknown. We will comprehensively assess oligodendrocyte function in post-mortem tissue and then interrogate mechanisms of dysfunction using a highly innovative stem cell model whereby we take MND patient stem cells and turn them into mini-brain structures in the lab. Identifying the cause of altered myelination and energy production will address a gap in current knowledge and highlight the relevance of oligodendrocytes when searching for effective therapies. |
| 2019 | Associate Professor Nimeshan Geevasinga Western Sydney Local Health District, NSW |
Utilising novel MRI connectomic analysis to explore pathophysiological changes in ALS
Understanding the exact pathophysiological processes underlying ALS progression remains elusive. We propose utilising magnetic resonance imaging (MRI) based “Connectomics”, a cutting edge field in neuroimaging which conceptualises the whole brain as an interconnected network, to explore changes in patients with familial and sporadic ALS. Connectomics uses both structural and functional connectivity information to build a map of the interregional connections within the brain. We hope to integrate MRI imaging with our expertise in neurophysiological and clinical evaluation of ALS patients with a view of learning more about the progression of ALS. Understanding the degenerative process in the brain may help to target specific pathways for therapeutic purposes. |
| 2019 | Professor Pamela McCombe University of Queensland, QLD |
Immunogenetics of motor neurone disease – a pilot study In patients with MND, there is variability in disease progression. There is also activation of the immune system. This occurs in the brain, where there is inflammation around the damaged motor neurones. There is also activation of the white blood cells and inflammatory proteins in the blood. This activation is associated with disease severity. Because of genetic differences, people vary in their ability to activate the immune system. In this novel study we will examine genetics of the immune-related genes in MND and see whether this can be correlated with disease severity. |
| 2018 | Dr Dominic Hare Florey Institute of Neuroscience and Mental Health, VIC |
The elemental signature of motor neurone disease All life is a mixture of chemical elements. Everything cells do result from precisely balanced ratios and reactions of nearly 30 essential elements. Disease must also start as chemical reactions and disturbances of this delicate equilibrium. Using advanced technology, minuscule shifts in element ratios can be mapped and measured to determine how, when and where chemical reactions that cause MND happen. Capturing the unique ‘elemental signature’ of MND will both help understand how essential elements like copper, iron and zinc are involved in MND, and provide a new laboratory test that may detect MND years earlier than currently possible. |
| 2018 | A/Prof Justin Rubio University of Melbourne |
A precision genomics approach to dissect the pathogenesis of MND
Genetic research has revealed important insight into the causes of MND, but there is still much to learn. We propose that the DNA genome of surviving neural cells in people who died from MND contains “hidden” information about the causes and progression of disease. To “unlock” this genomic information we have developed the means to isolate and interrogate the entire genome of single neurons from brain tissue donated for research. We expect that this research will improve understanding of MND biology and ultimately lead to the identification of new drug targets. |
| 2017 | A/Prof Mark Howard Institute for Breathing and Sleep |
Translation of respiratory biomarkers into MND practice The inability to breathe is unfortunately the most common cause of death in people living with motor neurone disease. Our research group reported that breathing assistance using non- invasive ventilation (NIV) increases survival by 13 months. Importantly, respiratory muscle strength appeared to identify the best time to start NIV. We propose to use 25 years of Australian Motor Neurone Disease Register data to confirm our preliminary findings. These experiments will enable clinicians to advise individual people with MND about when breathing assistance should be started to maximise benefit and assist researchers to optimise the design of therapeutic trials in MND. |
| 2017 | Prof Victoria Flood The University of Sydney and Westmead Hospital, Western Sydney Local Health District |
The effects of active exercise combined with an enriched diet on swallowing, speech function and weight in patients with MND; a randomised trial Eating, drinking and speaking are an important part of our life and patients with MND experience a rapid decline in these functions. Research suggests that active exercise might prolong the ability to eat and drink safely and prolong the ability to speak, however no thorough research has been conducted. Other research suggests that changes in diet might slow the progression of MND, with improved maintenance of weight status and muscle function. This study will be the first to evaluate the effects of these diet changes in patients with MND combined with active exercising on swallowing function, speech and weight status. |
| 2016 | A/Prof Tracey Dickson The University of Tasmania |
A systematic human pathology analysis of interneurons in MND In preliminary studies in our laboratory we have discovered that in a subset of MND human brain cases there is a loss of a certain type of neuron known as the interneuron. Not all cases show this loss. In this investigation we will perform systematic pathological analysis in a much larger set of human post-mortem MND tissue, sourced through the Oxford Brain Bank and the Australian Brain Bank Network. This will allow us to determine which types of cases show this specific type of cell loss and importantly our experiments will determine if interneuron pathology precedes, and therefore could be a trigger for, motor neuron pathology and cell death in the brain and/or the spinal cord, causing MND. |