MND Research Australia grants commencing 2023

Lead investigator: Dr Catherine Blizzard
Institution: University of Tasmania
Title: A collaborative multivariable approach to prevent the spread of corticomotor dysfunction in ALS

The most frequent presentation of a patient with ALS is increased motor cortex hyperexcitability and cytoplasmic build-up of TDP-43. It remains unclear how these pathological hallmarks lead to the widespread destruction of the corticomotor system. Our preliminary data indicates that TDP-43 in the cytoplasm may be causing neuronal hyperexcitability in the brain. We propose to discover (1) the cell signalling pathways through which TDP-43 triggers hyperexcitability, (2) how hyperexcitability spreads through the network, (3) if different regions require excitability to be selectively and differentially treated. This project may establish a novel and targeted drug delivery approach for patients with ALS.

Lead investigator: Dr Jeremy Lum
Institution: University of Wollongong
Title: Identifying drivers that contribute to the loss of neuronal connections in the early stages of ALS

Motor neurons contain important extensions used to form connections with other neurons and muscles. One of the earliest changes in ALS are the degeneration of these extensions, leading to an inability to effectively communicate, ultimately causing to paralysis. This project will focus on identifying the disrupted biological networks that lead to the loss of these extensions and look to find therapeutic targets to restore these connections in patient-derived cells and animal models of ALS.

Lead Investigator: Dr Alison Hogan
Institution: Macquarie University 
Title: The RNA-binding protein SFPQ offers a novel avenue to understand disease mechanisms and identify therapeutic targets in MND

Dysregulation of a new protein, SFPQ, has recently been linked to MND, presenting an exciting new opportunity to understand disease biology from a fresh perspective. This project will be among the first in the world to examine how SFPQ interacts with other key MND proteins and how these interactions contribute to disease progression. This will provide insight into disease biology and offer a new direction to identify novel interactions and targets for therapeutic modification.

Lead investigator: Professor Trent Woodruff
Institution: University Queensland
Title: Linking C9orf72 dipeptides to inflammation in MND

Mutations in the C9orf72 gene are the most common genetic cause of both familial and sporadic MND. One of the consequences of these mutations is the formation and accumulation of toxic products, termed dipeptides. It is currently unclear how these dipeptides lead to motor neuron degeneration. We have evidence that these dipeptides can activate the brain’s immune cells so that they release substances that are toxic to neurons. In this project, we will examine exactly how this happens and then test drugs that can stop this process in order to find new MND treatments.

Lead investigator: Dr Jennilee Davidson
Institution: Macquarie University 
Title: Characterising the interactome of sequestosome-1 (p62) – the peacemaker between protein homeostasis and dysfunction

Protein clearance pathways and aggregate formation have recently been associated with dysfunctional protein/RNA foci formation (biomolecular condensates). One protein commonly identified in aggregates in ALS is Sequestosome-1/p62. This study will combine proteomic, optogenetic and bioinformatic approaches to investigate how p62 biomolecular condensates are involved in ALS states. This study aims to identify how p62 domains and ALS-linked proteins alter the protein interactors of p62, which disrupt its biomolecular properties, leading to protein aggregation. These studies will provide valuable insight into a newly described process in ALS and potentially identify a therapeutic target to be leveraged for ALS treatment.

Lead investigator: Dr Shu Yang
Institution: Macquarie University
Title: Characterising CHCHD10-mediated TDP-43 mitochondria entry in MND

Mitochondria are the powerhouse of all cells in our body. Healthy mitochondria generate energy and determine the life-death fate of the cell. In MND, mitochondria can be harmed by a key disease protein called TDP-43, which does not usually reside in the mitochondria. In MND, it can enter mitochondria and cause damage. We recently found a new protein that can control whether or not TDP-43 enters mitochondria. In this study, we will identify the mechanism behind this phenomenon in a unique new MND cell model and determine if this protein can safeguard mitochondria from TDP-43’s damage. This will provide new avenues for therapies. 

Lead investigator: Associate Professor Mary-Louise Rogers
Institute: Flinders University
Title: Refinement of p75 ^ECD measurement as a biomarker for clinical trials for MND

Our grant aims to improve the measurement of a strong candidate MND biomarker, p75^ECD in urine and blood. By developing a more sensitive Single Molecule Array assay we will improve and expand use of urinary p75^ECD for clinical trials and improve quantification in the blood. This will pave the way for p75^ECD to be used in more widely in clinical trials to determine effective treatments.

Lead investigator: Dr Rosie Clark
Institute: University of Tasmania
Title: Releasing inhibitions – a novel approach to determine targets of inhibitory dysfunction in ALS

Within the brain of people with ALS/MND, there is a change in the balance of the normal neurotransmitters that are required to ensure motor neurons don’t become overactivated, which can lead their dysfunction and death. This imbalance may be driven by a reduction in the level of the main inhibitory neurotransmitter in the central nervous system, GABA. In this project we will drive reduced GABA in an ALS model to determine how it affects the disease process and importantly what pathways may be likely targets to help restore reduced GABA function in people with ALS.

Lead investigator: Dr Fleur Garton
Institution: University of Queensland
Title: An Australian Sporadic ALS transcriptome resource

The human genome is made up of thousands of genes that are processed into RNA to control the expression of proteins. Resources that profile the genome in ALS exist, but those that include RNA are lacking. Given altered RNA transcription is implicated in ALS via genes (i.e. TARDBP, FUS) and proteins (i.e. TDP-43) this resource is needed. Here we aim to establish an Australian Sporadic ALS transcriptome resource. Blood samples with matched genomic information will help to identify novel transcript expression events contributing to ALS. This could support the discovery of novel mechanisms of disease and therapeutic avenues.

Lead investigator: Dr Rita Mejzini
Institution: Murdoch University
Title: Development of RNA-like precision therapies to reduce toxic MND protein in the neuron

Mutations in the FUS gene contribute to motor neurone disease (MND) cases including early onset and juvenile MND. In these patients, the FUS protein mislocalises, aggregating and becoming toxic to the neuron. Everyone has two copies of the gene and if only one copy carries a mutation, patients are affected by MND. We have begun development of innovative, therapeutics that target only the mutant copy of the FUS gene, stopping the production of toxic protein and allowing the unaffected copy to produce normal protein to fulfil its functions. This project will involve continued development of these potentially disease altering therapeutics.

Lead investigator: Associate Professor Peter Noakes
Institution: University of Queensland
Title: Stabilising Neuromuscular Signalling in Motor Neuron Disease

Muscle from MND patients responds poorly to the motor nerve induction factor agrin. Agrin binds to the muscle receptor LRP4 that signals the muscle to stabilise motor nerve muscle connections. Further, our studies have revealed that LRP4 expression has dropped in MND muscle, which might explain its poor response to agrin. We plan to overexpress LRP4 protein in MND muscle to rescue its poor responsiveness to agrin. LRP4-Lenti virus will be used to transfect MND and non-MND muscle. These transfected muscle cells will also be used in motor neuron co-cultures to determine if we have improved neuromuscular connections.

Lead investigator: Associate Professor Sean Millard
Institution: University of Queensland
Title: Understanding how the ALS risk factor, GGNBP2, impairs a cellular process defective in many people with ALS

Overexpression of the GGNBP2 gene increases the risk of getting ALS. We have been studying this gene in the fruit fly to better understand how it contributes to disease. Importantly, fly mutants that lack this gene and exhibit motor neuron defects can be completely rescued with the human gene. This argues strongly that GGNBP2 has similar functions in fly and human motor neurons. We found that GGNBP2 plays a role in a process commonly impaired in ALS that removes aggregated proteins and damaged organelles from a cell (autophagy). This grant will determine how it impacts this process and whether drugs that promote autophagy can rescue phenotypes observed in flies overexpressing GGNBP2. Given the number of genes involved in ALS that have been linked to autophagy, therapies that target this process have the potential to benefit many people with this disease.

Lead investigator: Dr Duncan Crombie
Institution: University of Melbourne
Title: 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.

Lead investigator: Dr Brooke-Mai Whelan
Institution: University of Queensland
Title: Save Our Speech (SOS) Study

People with MND frequently ask speech pathologists “How long will it be before I lose my speech?” and “Can you stop me from losing my speech?”. The answers to these questions remain largely unknown. The ability to accurately predict the rate and pattern of speech loss in MND remains limited with currently available assessment tools. This research aims to better understand speech changes in MND using state of the art computerised analysis of speech over time. The findings will provide scientific markers of speech change in ALS related to declines in communication effectiveness. This information will allow Speech Pathologists to more accurately predict time to speech loss in MND, and provide a data framework from which patterns of treatment responsiveness may be determined.

Lead investigator: Professor Aaron Russell
Institute: Deakin University
Title: Investigating the role of neurturin (a specific protein) as a therapeutic strategy to delay ALS disease progression

This study will investigate whether increasing the levels of a specific protein (called neurturin) in a mouse model of human ALS delays disease progression. We expect disease progression to be slowed down because changes to the skeletal muscle environment that will allow connections that transmit signals between the brain and the muscles are maintained for longer. This would allow the ALS mice to maintain better coordination and strength. If our research findings are translatable to people with ALS then it would delay their disease progression, extend their independent living and their quality of life. 

Lead investigator: Professor Mark Wilson
Institution: University of Wollongong
Title: Identifying new drugs from Australian native plants and animals to treat motor neuron disease.

During the disease, MND patient nerve cells that control muscles are slowly killed as a result of proteins that stick together inside these cells to form visible lumps. This leads to a progressive loss of muscle control during the disease. Using a high throughput drug screening platform, we have already tested thousands of chemical fractions prepared from unique Australian animals and plants, to identify several that potently reduce the number of protein lumps inside nerve cells. This project will chemically identify active drug molecules from Australian plants and animals and test their suitability to become new treatments for MND.

Lead investigator: Dr Sonam Parakh
Institution: Macquarie University
Title: Nucleoredoxin (NRX), a novel gene therapy target against TDP-43 multifaceted pathogenic mechanisms.

pecific molecules have the ability to regulate oxygen levels in the brain. However, during MND, oxygen rich species increase, which induces neurodegeneration. We have identified a novel molecule, nucleoredoxin (NRX), that is a global regulator of oxygen species in cells and is protective in MND. Gene therapy approaches are showing great promise for neurodegenerative disorders, and using a completely new strategy, we will examine if delivering NRX is protective against disease onset/progression in mice that develop MND. This study will therefore examine if delivering NRX by this strategy has potential as a new treatment for MND in the future.

Lead investigator: Dr John Lee
Institution: University of Queensland
Title: Therapeutic potential of targeting one of the core players of inflammation (Inflammasome) in MND

One component of our immune system that is gaining attention as a key disease driver for MND is ASC. We believe that unwanted activity of ASC is contributing to MND pathology. This study will investigate the role of ASC in immune cells of MND patients and use second generation drug developed by our industry collaborator to reduce ASC expression in mouse models of MND. This will allow us to understand if reducing ASC can dampen immune response and ultimately protect motor neurons. This will help determine whether targeting ASC may be a viable therapeutic option to benefit people with MND.

Lead investigator: Dr Adam Walker
Institution: University of Queensland
Title: Finding enzymes to remove MND pathology from neurons

This collaborative project between the University of Queensland and Macquarie University will use high-throughput experiments to identify enzymes that modify the pathological proteins that accumulate in nerves of people with MND. Testing human neurons grown in a dish, as well as brain samples from MND mice and people who have passed away from MND, these experiments aim to identify new approaches to stop pathology forming. In the future, this work could guide development of new drugs to treat MND.

Lead investigator: Dr Derik Steyn
Institution: University of Queensland
Title: Decoding disease impact on the hypothalamus across the ALS-FTD spectrum of disease

Rapid weight loss is associated with faster disease progression and earlier death in patients with ALS. There is evidence to suggest that the hypothalamus (a small part of the brain that regulates body weight) might be impacted by disease. Using a very new technique to map gene expression in individual cells in human brain samples, this project will uncover how disease impacts the hypothalamus in patients with ALS and FTD. Results will improve understanding on why some patients experience weight loss, and how processes associated with ALS and FTD may differentially impact the function of cells within the human brain.

Lead investigator: Dr Margreet Ridder
Institution: University of Queensland
Title: Drug Controlled Gene Therapy for Motor Neurone Disease

Hyperexcitability of motor neurons is seen in all forms of motor neurone disease (MND) just prior to motor neuron death. Researchers have been controlling the excitability of defined neuronal populations with drug activated receptors in order to study their role in behaviour. We will use this same technology, not to study function,but to reduce motor neuron hyperexcitability. We will express our novel neuronal silencing receptor in motor neurons of MND mice. If effective in increasing motor neuron survival, our receptor is already optimised for human clinical use and is activated by ivermectin, a safe FDA-approved drug.

Lead investigator: Elise Kellet
Institution: Queensland Brain Institute, University of Queensland
Title: The role of post-translational modification of TDP-43 in disease pathology

MND is characterised by the aggregation of proteins in upper and lower motor neurons. The main aggregating protein experiences different chemical changes in disease. While initially believed to drive disease progression, recent findings question whether these changes may instead be protective. My research investigates the role of chemical alterations of this protein in disease pathology by identifying upstream proteins that regulate the alterations and exploring downstream consequences. My aim is to improve our understanding of MND pathology and identify new processes for therapeutic targeting to help people living with MND.

Lead investigator: Kathryn Maskell
Institution: University of Tasmania
Title: Do upper and lower motor neurons need different treatments to effectively stop neurodegeneration in ALS?

ALS involves degeneration of both the upper motor neurons in the brain and lower motor neurons in the spinal cord, but we still don’t understand how degeneration starts and spreads between them. Upper and lower motor neurons have different characteristics and reside in different environments, new evidence suggests that they are differentially vulnerable to disease mechanisms in ALS. Importantly, the two populations may need different therapeutic support to prevent disease progression. This research aims to interrogate the vulnerabilities of upper and lower motor neurons to disease mechanisms of ALS and will inform our approach to treating patients suffering from ALS.

Lead investigator: Aida Viden
Institution: University of Melbourne
Title: Investigating the anatomical origins of MND

MND is caused by the death of both brain and connecting spinal motor neurons (MNs). Importantly, transmission of disease amongst MNs propagates in a cascade. Our current understanding of the mechanism and direction of pathological spread between brain and spinal MNs is limited. This PhD project aims to determine the primary site of disease initiation in MND with the use of a gene-editing approach targeting brain and spinal MNs individually in a clinically relevant MND mouse model. By understanding which MNs transmit disease and how, we can inform new therapeutic interventions targeting brain and/or spinal MNs to prevent further spread.

Lead investigator: Jeryn Chang
Institution: University of Queensland
Title: Decoding the loss of appetite and pathophysiology of the brain in motor neuron disease

The loss of appetite is observed in patients with MND. This is clinically important, as energy deficits and weight loss are associated with faster disease progression and earlier death. My studies aim to identify the impact of MND on the hypothalamus, a small area of the brain that regulates appetite, and how this may contribute to functional deficits throughout the brain. Studies aim to provide a biological basis for the loss of appetite in patients with MND, which will enhance understanding of disease, and provide insights to better manage care strategies aimed at improving quality and duration of life.

Lead investigator: Sean Keating
Institution: Queensland Brain Institute, University of Queensland
Title: TDP-43 and protein clearance in the pathogenesis and treatment of MND

In MND, toxic clumps of proteins accumulate within the brain and spinal cord, leading to neurodegeneration. Using human MND tissue, neurons grown in a dish, and genetically modified MND mice, I aim to investigate how dysfunctional cellular “waste removal” systems cause protein clumping in neurons. I also aim to discover new ways to effectively stimulate these “waste removal” systems with drugs and gene therapies, and determine whether this can increase the break-down of toxic protein clumps and protect against disease. By stopping protein clumping, we aim to extend neuron survival as a therapeutic strategy to treat people living with MND. 

Lead investigator: Katherine Lewis 
Institution: University of Melbourne
Title: Characterising Myelin Changes in Motor Neuron Disease

Despite garnering much deserved attention and funding, the primary causes underlying MND onset and progression remain elusive. This, in part, may be due to most MND research being conducted with a neuroncentric focus. We know that motor neurons are encased in a lipid-rich sheath termed myelin, which is essential for neuronal health and survival. We also know that the cells that produce the myelin have been shown to exhibit MND pathology. However, the exact role of myelin-producing cells in MND remains unclear and it is unknown to what degree their dysfunction contributes to MND onset and progression. Thus, this PhD project aims to comprehensively characterise myelin changes in MND over the course of disease, using clinically relevant mouse models, complemented with sophisticated stem cell derived ‘mini brain’ model systems. By understanding the role of myelin in MND, we can provide insight into new treatment avenues and therapeutic targets to preserve motor neuron health and function.

Lead investigator: Jianina Marallag
Institution: University of Queensland
Title: The potential role of CXCR2 activation in motor neuron disease

Excessive activation of the immune system has been found to result in motor neuron death in MND. CXCR2 is a cellular receptor that is gaining interest for its involvement in recruiting immune cells to the site of injury. Inappropriate activation of this receptor may contribute to the progression of MND. This project will utilise a drug that blocks CXCR2 in mouse models of MND and patient samples to investigate if it is able to protect motor neurons by reducing immune system activity. The results will help determine if CXCR2 can be used as a therapeutic target for MND patients.

Lead investigator: Natalie Grima
Institution: Macquarie University 
Title: Investigating novel genomic and transcriptomic features of sporadic MND

MND is marked by substantial heterogeneity and it is therefore likely that personalised therapeutic strategies will be required. However, for the 90% of patients classified as having sporadic MND, the biological factors affecting development and progression remain largely unresolved. This project aims to identify novel risk and protective factors associated with sporadic MND, providing new targets for diagnosis, research and treatment. It will employ cutting-edge genomic and transcriptomic strategies to an extensive and unique collection of patient samples to look for complex genetic variants and gene expression changes associated with disease onset and/or variable development of the hallmark TDP-43 pathology.

Lead investigator: Dr Anna Ridgers
Institution: Austin Health
Title: Virtual Ventilation: An evaluation of the utility of ventilator-recorded data to titrate ventilator settings in comparison to non-invasive ventilation polysomnography

Home ventilation with non-invasive ventilation (NIV) is used to support breathing in respiratory (breathing) failure due to muscle weakness in motor neuron disease. Patients require different ventilator settings to optimally support breathing and improve symptoms and survival. Settings are based on daytime assessment, with subsequent overnight laboratory sleep study and face to face appointments. This is important for successful NIV but can be burdensome for patients and their carers. Newer generations of NIV record information that clinicians can review remotely. This study aims to assess whether remotely recorded ventilator data could be used to optimise ventilator settings without having to rely upon a hospital sleep study, providing the scientific foundation for remote, patient centred models of care.

Lead Investigator: Associate Professor Parvathi Menon
Institution: University of Sydney
Title: Improved Understanding of Brain Excitability in ALS/MND

Cortical hyperexcitability, is an important mechanism underlying MND which contributes to nerve degeneration and consequent muscle wasting, varying MND types, adverse prognosis, and disease progression. Mechanisms underlying cortical hyperexcitability in MND are partially understood and their limitation or reversal may be vital in MND management. Loss of inhibitory interneurons has been proposed as a mechanism for cortical hyperexcitability in mouse models. This research project will help prospectively interrogate the function of distinct cortical interneuron populations in sporadic MND patients using unique cortical stimulation techniques to improve understanding of this key pathogenic mechanism.

Lead investigator: Dr Fiona Bright 
Institution: Macquarie University
Title: Exploring undefined regions & novel functions of the TDP-43 protein - The molecular pursuit to uncover the cause and ultimately find a cure for MND

In 95% of MND patients, abnormal protein deposits of TDP-43 are present within cells of the brain, and spinal cord. The molecular mechanisms underlying TDP-43 pathology in MND remains unknown. The structural parts of TDP-43 containing disease-causing mutations have undergone detailed studies, yet the remaining part is significantly understudied. Importantly, this part contains TDP-43’s transport and protein binding machinery with ample opportunity to learn about its physiological movement within the brain and spinal cord. Novel regulators of TDP-43 transport, and other functions awaits discovery. This project will explore undefined regions and molecular pathways of TDP-43 which holds the key to understanding what goes wrong in MND.

Lead Investigator: Dr Mouna Haidar
Institution: Florey Institute of Neuroscience and Mental Health
Title: A novel gene therapy approach targeted to overactive brain motor neurons

There is increasing evidence that motor neurons in the brain are electrically overactive in MND, leading to damage of motor neurons in the spinal cord. We will evaluate a new gene therapy approach targeting motor neurons in the brain to reduce their overactivity in MND. Using "designer receptor" technology, we will test this approach in motor neurons grown from MND patients and mouse models. We predict that our gene therapy strategy will reduce the burden of electrical overactivity in the brain, preserving motor neurons and correcting these models, supporting future development of designer receptor therapy for MND.

Lead investigator: Dr Marnie Graco
Institution: Institute for Breathing and Sleep, VIC
Title: Optimising quality of life and survival in motor neurone disease by improving the use of overnight breathing support

Supporting breathing overnight with non-invasive ventilation improves life expectancy in motor neurone disease (MND). However only 19% of Australians living with MND currently access the treatment. This research will directly address this problem, by: 1) understanding the barriers to the uptake of non-invasive ventilation from the perspective of people living with MND, their carers / family and clinicians; 2) carefully designing a strategy that targets these barriers; and 3) implementing and testing the effectiveness of this strategy in a single Australian location. This research will optimise quality of life and survival in MND by improving the uptake of non-invasive ventilation.

Lead investigator: Dr Thomas Shaw
Institution: University of Queensland
Title: Ultra-High Field MRI of Spinal Cord Tissue in Motor Neurone Diseases

Characterising differences in MND sub-types including ALS and PLS is important for understanding the disease. This project aims to distinguish these sub-types, which have separate patterns of brain and spine pathology. To achieve this, I will use Magnetic Resonance Imaging to measure tissue properties of brain and spine over time in MND patients, comparing these with clinical outcomes of disease. The project will generate significant outcomes by - for the first time - relating pathology in the brain and spinal cord to MND sub-types over time. This will increase understanding of mechanisms accounting for the irreversible progression of MND.

Lead Investigator: Dr Emily McCann
Institution: Macquarie University 
Title: Investigating the role of complex genomic variation in MND

Gene mutations are the only known cause of MND, however almost 90% of patients have an unidentified genetic cause of MND. Little is also known about why the clinical presentation of MND varies substantially between patients. In this project, I will use innovative bioinformatic strategies to search through the genomes of MND patients to find complex genomic changes that play a role in the cause, onset and progression of MND. Once identified, these MND-relevant genomic changes will provide clues to how MND develops and progresses, to help patients and clinicians make informed decisions about treatment and family management strategies.

Lead investigator: Dr Nicholas Geraghty 
Institution: University of Wollongong
Title: High-throughput flow cytometry drug screen to discover new treatments for MND

Motor Neurone Disease (MND) arises due to proteins misfolding inside motor neurone cells, leading to toxicity, cell death and loss of motor function. TDP-43 is an important protein known to misfold, leading to its clumping or “aggregating”, which causes cell death and leads to MND. This project uses a cell model in which TDP-43 forms toxic aggregates, in a high-throughput drug screen of thousands of chemicals to find potential drugs to treat MND patients. A small number of “hits” have already been identified and will be screened in animal models of MND, to identify a therapeutic to treat MND patients.