MND Research Australia grants commencing 2024

Lead investigator: Dr Chien-Hsiung (Alan) Yu
Institution: University of Melbourne
Title: Investigating TDP-43-associated immune activation to map the causes of MND

The aberrant build-up of proteins is a common feature of neurodegenerative diseases, including MND. Elucidation of the mechanisms involved in this protein build-up is therefore a key goal in order to develop therapeutic strategies that can effectively slow or prevent progression of this disease. This project investigates the role of dysregulated immune function in causing protein build-up and disease progression in MND, by bring together interdisciplinary expertise across Australia and internationally. Technology that enables unprecedented analysis of cellular and molecular signals within their native context will be used to understand the causes of disease and foster novel therapeutics.

Lead investigator: Dr Rachel Atkinson
Institution: University of Tasmania
Title: Freezing MND in its tracks

When our core body temperature is cooled, our body activates a natural protective mechanism known as the ‘cold stress response’. This mechanism helps to protect the nervous system by slowing down metabolism and safeguarding cell structures. The cold stress response is used by mammals that hibernate during winter, and is also activated in humans during therapeutic cooling when used following stroke and spinal cord injury. During my fellowship, I plan to explore whether this ancient and conserved pathway can aid in protecting nerve cells in motor neuron disease. I will use various approaches such as mimicking therapeutic cooling or using state-of-the-art drugs called ASOs to directly stimulate the proteins involved in this pathway.

Lead investigator: Dr Nicole Sheers
Institution: University of Melbourne
Title: Developing a new exercise therapy to improve breathing and cough in people living with MND

Over time, people living with MND lose the ability to take deep breaths and cough. This research will test a new respiratory training therapy that aims to help people living with MND take bigger breaths and strengthen their cough. We will work out how best to measure cough and work with people with MND and their health care team to test the i) feasibility, ii) acceptability, and iii) benefits of the new treatment. With these answers we will then test if our new treatment definitely improves breathing, coughing, symptoms, and quality of life for people living with MND.

Lead investigator: Dr Thais Sobanski 
Institution: The University of Queensland  
Title: Boosting sugar breakdown to halt the progression of MND 

Cells use sugar as a key energy source to fuel function. This project will study how the breakdown of sugar can impact a critical pathway in cells that is used to repair damaged DNA. In ALS, cells do not use sugar and or repair their DNA effectively, but it is not known if these two processes are linked. This project will tweak sugar breakdown to see if it can improve the way that motor neurons repair their DNA, and if it can improve their survival. We aim to use this knowledge to identify novel interactions and targets to develop new treatment options to improve outcomes for people living with ALS. 

Lead investigator: Dr Adekunle Temitope Bademosi
Institution: University of Queensland
Title: Investigating the role of synaptic proteins in MND neurodegeneration

A key feature of MND is the mislocalization and aberrant clumping of TAR DNA-binding protein-43 (TDP-43). The toxicity induced by these clumps results in neuronal damage. However, the mechanistic link between TDP-43 and neurodegeneration is largely unknown. TDP-43 is involved in RNA metabolism and many of these RNAs code for the expression of proteins at the synapse. A potential mechanism for neurodegeneration in MND is that the loss of TDP-43 function leads to detrimental changes in the function of these synaptic proteins. We therefore seek to characterize how changes in the abundance and function of the synaptic proteins impacts neurodegeneration.

Lead investigator: Dr Samantha Barton
Institute: University of Melbourne
Title: Could Schwann cells be exacerbating motor neuron dysfunction in MND?

Motor neurons have an insulating coating called myelin, which is essential for their function. Myelin is produced by Schwann cells. We hypothesise that Schwann cells may not function properly in MND and their myelin may not be supporting motor neuron function. We will comprehensively characterize Schwann cell function in a combination of relevant TDP-43 MND mouse models coupled with a human stem cell ‘mini-brain’ model to investigate how Schwann cells contribute to MND. By characterizing their contribution in MND, we propose a potential druggable target – if we preserve Schwann cell function, could we also rescue motor neuron function?

Lead investigator: Dr Mouna Haidar
Institute: University of Melbourne
Title: Assessing the therapeutic impact of chemogenetic stimulation of neuropeptide Y cortical interneurons in ALS mouse models

The activity of brain motor neurons is modulated by inhibitory neurons or interneurons, whereby reduced interneuron activity is associated with motor neuron overactivity. Indeed, cortical interneurons are lost in ALS patients and mouse models. One way to attenuate overactive brain motor neurons is to increase the activity of cortical interneurons. We will use excitatory chemogenetics targeted to a neuropeptide expressing cortical interneuron in an ALS mouse model and assess the therapeutic impact on (i) cortical activity, (ii) motor symptoms, disease progression and survival, and (iii) neuropathology. This study will establish whether targeting cortical interneurons is a potential therapeutic target for ALS.

Lead investigator: Dr Wei Luan
Institution: University of Queensland
Title: Synaptic mechanisms of non-motor dysfunction in MND

The majority of people living with MND develop non-motor symptoms including cognitive changes. However, the mechanisms controlling these non-motor changes remain largely unclear, and there are no therapies to address this important aspect of MND. In this proposal, we will investigate how motor and non-motor phenotypes develop during disease in a mouse model reminiscent of human MND. We will test whether drugs modulating neuronal signalling in the brain can reverse non-motor dysfunction in these mice. Overall, these studies will define whether non-motor phenotypes can be ameliorated in MND mice, revealing potential avenues to therapy for people living with MND.

Lead investigator: Dr Sarah Rea
Institution: Murdoch University
Title: Antisense oligonucleotide induced clearance of cytoplasmic TDP-43 aggregates to prevent disease progression in ALS

Sporadic cases present similarly at the clinical and cellular levels. Most MND cases (~97%) have cytoplasmic TDP-43 aggregates in neurons. Introducing TDP-43 aggregates into cells or animals is sufficient to induce MND phenotypes. Mutant SOD1 aggregates cause 2-3% of MND. We developed a drug that activates the clearance pathway, autophagy and removes ~50% of SOD1 aggregates in our cell models. This study will determine if our drug also clears TDP-43 and can reduce disease progression in a TDP-43 animal model.

Lead investigator: Dr Luke McAlary
Institution: University of Wollongong
Title: 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.

Lead investigator: Dr Ianthe Pitout
Institution: Murdoch University
Title: Developing a New Drug Candidate for C9ORF72-linked Motor Neuron Disease

Mutations in the C9ORF72 gene are a common cause of familial MND. We have developed a genetic drug candidate to 'switch off' the toxic part of the C9ORF72 gene. Here, we will comprehensively test our molecule in specialised “brain-cells-in-a-dish” grown from MND patient cells and in MND mice. We predict our molecule will reduce toxicity in the brains of MND mice, providing hope for a powerful new therapy for C9ORF72-linked MND sufferers. Despite recent clinical failures for C9ORF72-MND investigational drugs, our novel genetic designer drug provides another opportunity to deliver impact to patients.

Lead investigator: Dr Sayanthooran Saravanabavan
Institution: Macquarie University 
Title: Examining the pathogenic roles of circular RNAs in genomic instability in ALS

Genomic instability in motor neurons is fundamental to the origin and repercussions of ALS pathology, therefore an ideal target for preventative interventions. A paradigm shift in the past decade revealed that non-coding RNAs are essential for safeguarding the genome’s integrity. Notably, ALS-associated proteins are central players in RNA metabolism, suggesting a link between genomic instability in ALS and the realm of RNA. This project will examine the role of circular non-coding RNA in ALS and advance insights into its causes, proposing both strategies to tackle genomic instability in ALS and pinpointing novel genes for intervention against associated pathology.

Lead investigator: Dr Rachel Tan
Institution: University of Sydney
Title: Accessible disease-specific biomarkers for sporadic MND

The ability to match each patient with MND to a relevant treatment targeting the specific underlying pathology is critical for successful drug development and intervention. This proposal studies the blood samples, brain and spinal cord from patients who have been followed longitudinally to autopsy to identify blood biomarkers of underlying pathology. It is focused on sporadic MND and harnesses a wealth of longitudinal clinical and pathobiological data to significantly advance current understanding of sporadic disease pathogenesis to accelerate the identification and treatment development process for this insidious disease.

Lead investigator: Dr Benjamin Trist
Institution: University of Sydney
Title: Partnering with industry to develop new assays for improving diagnosis, understanding and treatment of ALS

Atypical forms of superoxide dismutase 1 (SOD1) protein contribute to cell death in ALS and are the target of several clinical trials. Measuring these abnormal proteins may also help us to identify the disease and track its progression. However, no commercially-available assays exist for this target. In partnership with leading Australian assay company, TGR Biosciences, we aim to develop assays for measuring atypical SOD1 protein in cell and animal models of ALS, as well as in ALS patient blood and cerebrospinal fluid samples collected in the clinic. This project will produce innovative tools with the potential to improve diagnosis, understanding and treatment of ALS.

Lead investigator: Professor Yuling Wang
Institution: Macquarie University
Title: Investigating the role of extracellular vesicles (EVs) membrane

Extracellular vesicles (EVs) are microscopic capsules secreted by all cells. Their main function is to deliver information molecules between cells. EVs are known to spread pathological MND proteins, including misfolded TDP-43, from one motor neuron to another. The ability of CNS EVs to transport cargos to specific neurons, and cross the brain barrier, offers potential for biomarker and drug development. We will compare healthy and MND neuron-secreted EVs to discover distinct proteins that determine EV destination. This will enable us to understand how EVs mediate the progression of MND and how EVs can be harnessed for diagnosis and targeted drug delivery.

Lead investigator: Associate Professor Richard Gordon
Institute: Queensland University of Technology
Title: Harnessing the immune system to resolve neuroinflammation and promote motor neuron survival in MND

Persistent inflammation and immune system hyperactivity are major contributors to motor neuron loss and disease progress in MND. Breaking the cycle of inflammation to enable survival of vulnerable motor neurons is an attractive therapeutic strategy to slow MND progression. The majority of therapeutic approaches targeting inflammation have focused on blocking pro-inflammatory mechanisms. However, this approach has failed to demonstrate efficacy in human trials to slow or stop MND progression. This project will explore a radical new approach of harnessing the innate immune system to resolve inflammation and promote motor neuron survival by activating an endogenous protective pathway (Dectin-1). These proof-of-concept studies will provide the basis for developing a new class of therapies for MND targeting endogenous pathways which can suppress and resolve inflammation and drive motor neuron survival and possibly even regeneration of dying neurons.

Lead investigator: Dr Cindy Maurel
Institution: Macquarie University
Title: Probing molecular drivers of TDP-43 phase transition: the influence of lysine modifications

The hallmark protein TDP-43 is found as aggregated clumps in 97% of ALS cases and therefore represents a promising therapeutic target. This proposal aims to provide crucial new knowledge of mechanisms driving this TDP-43 aggregation. We have developed and will apply an innovative set of techniques to assess the role of specific modifications that have emerged to drive such accumulation of TDP-43 in a living nerve cell. We will provide a comprehensive evaluation of how lysines modifications can influence pathology. This crucial knowledge may help to reduce TDP-43 burden.

Lead investigator: Associate Professor Marco Morsch
Institution: Macquarie University
Title: Targeting the nucleus: Is TDP-43 supplementation in the nucleus enough to delay disease progression?

In healthy motor neurons, the protein TDP-43 is mainly located in the nucleus. However, in ~97% of MND patients TDP-43 moves from the nucleus to the cytoplasm, forming clumps or aggregates. This mislocalisation coincides with the loss of TDP-43 from its original location, the nucleus. A fundamental question remains - what is the primary cause of this toxicity (cytoplasmic TDP-43 aggregation or nuclear loss) and how can we prevent it? This project will address this question by testing whether nuclear supplementation of TDP-43 is sufficient to delay disease progression – providing preclinical validation of a novel approach.

Lead investigator: Dr Hazel Quek
Institution: The Council of the Queensland Institute of Medical Research
Title: Microglia Diversity in ALS: Impact on Disease and Drugs

We're studying the complexity of immune cells, specifically microglia, in Motor Neuron Disease (MND). Utilising a 3D cell culture model of MND microglia and employing single-cell RNA sequencing, our objective is to pinpoint distinct types of microglia and comprehend their unique roles in the disease. Additionally, we are examining how these cells respond to drugs, with the goal of enhancing our ability to treat MND more effectively.

Lead investigator: Dr Alain Wuethrich
Institution: The University of Queensland 
Title: Developing a new nanotechnology to track ALS

To date, it has been difficult to develop therapies for ALS because there are few reliable biomarkers that can tell us about diagnosis, disease progression and outcome, whether someone will get ALS, and how someone with ALS responds to drug treatment. This project aims to develop a new nanotechnology for blood-based measurements of extracellular vesicles - the body’s natural nanoparticles - to see if they can provide key information to support diagnosis, and tracking of disease progression and outcome. We hope that this can also be used in future for testing drug responses in clinical trials.
 

Lead investigator: Dr Rebecca San Gil 
Institution: The University of Queensland 
Title: Targeting protein aggregation in motor neuron disease

Disease onset in all cases of MND involves the accumulation of damaged proteins that stick together forming toxic aggregates that trigger motor neuron death. The proposed research program will take advantage of new genetic engineering and imaging techniques to shine the light on a target protein that refolds and disposes of damaged proteins in human neurons. Proof-of-concept experiments will demonstrate whether refolding damaged protein back into a functional protein can slow or stop disease progression. This work will identify new strategies in targeting protein aggregates to prevent neurodegeneration for future application to develop therapies for people living with MND.  

Lead investigator: Dr Andrew Tosolini
Institution: The University of Queensland 
Title: Connecting the dots between the powerhouse of the motor neuron and their vulnerability in MND.

In MND, certain types of motor neurons are more susceptible to disease than others, but the cause of this selective vulnerability is not yet known. This project focuses on how the functions of mitochondria (the cells powerhouse) and metabolism (conversion of fuel into energy) are altered in motor neurons in MND. For the first time, we will use innovative technology to assess how clinically, or near-clinically, available drugs/compounds affect the mitochondria in motor neurons prone to disease. This project will result in crucial new knowledge about disease causes, which can improve the designing of new therapies for MND.

Lead investigator: Flora Cheng
Institution: Macquarie University
Title: Identification and characterisation of RNA-protein interaction in pathological aggregates of TDP-43 in MND

Amyotrophic lateral sclerosis is a devastating motor neuron disease without any cure to date. The proposed research will determine whether mutation in an important protein found in aggregates in ALS patients, TDP-43, exhibit altered RNA binding properties which leads to the formation of aggregation in cells. This could be a critical piece of information to a potential RNA-based therapeutic treatment to either reverse or prevent formation of those TDP-43 inclusions in ALS patients.

Lead investigator: Stephanie Howe
Institution: University of Queensland
Title: Characterising the spatio-temporal landscape of neuroinflammation and metabolism in ALS

Metabolic changes and neuroinflammation are some of the many pathways associated with worsening pathology in MND. Unfortunately, the sequence of events leading to neuronal death and the spread of disease require further elucidation. My PhD aims to use a variety of human clinical samples and data, mouse models and in vitro cell models of MND to help understand how inflammation contributes to metabolic changes and vice versa. My goal is to identify specific mechanisms of MND cell pathology and death, and to establish appropriate models for recapitulating the complex landscape of this disease.

Lead investigator: Andrew Quattrocchi
Institution: The University of Melbourne
Title: Understanding and modelling the neurovascular niche in health and Motor Neurone Disease

The health of our brain depends on the health of its blood vessels. In MND we know motor neurons that reside in the brain are uniquely vulnerable. What we do not understand is how the 640km of blood vessels in our brain which supply all our nutrients and oxygen, but also removes waste, may contribute to this motor neuron death. This project aims to comprehensively characterise vascular and neural changes in MND, using patient derived 3D human stem cell systems. By understanding how and what goes wrong in our blood vessels, this project is poised to inform a new generation of therapeutic strategies that targets both our vascular and brain health.

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: Dr Thanuja Dharmadasa
Institution: University of Melbourne and The Florey
Title: Exploring disease heterogeneity across MND clinical phenotypes using a multimodal, multicentre neuroimaging approach

This long-term study will build an integrative national network to use advanced brain neuroimaging and detailed clinical assessments to follow patients through their disease journey and identify different clinical subgroups. It is hoped this will significantly increase our understanding of disease mechanisms and develop imaging markers that can differentiate the MND subtypes. For people living with MND, this research will lead to better prediction of disease progress and spread, earlier as well as more specific implementation of management and treatment strategies. This knowledge can also inform the future design of clinical trials for the development of targeted treatment strategies.

The recipients of the Daniel McLoone Major Research Initiative are jointly funded by MND Research Australia (MNDRA) and FightMND.

Lead investigator: Professor Bradley Turner
Institution: University of Melbourne and The Florey
Title: Australian Preclinical Research ALS (APRALS) Network: a roadmap for effective translation of therapeutics for sporadic MND

This project will launch Australian Preclinical Research ALS (APRALS), a national collaborative network which aims to accelerate development of novel treatment candidates towards clinical trials in MND. The network will bring together distinct and advanced expertise in human stem cell technology and animal models of MND to develop a novel class of powerful DNA designer drugs targeting key aspects of sporadic MND. By targeting these key aspects of sporadic MND, the researchers will significantly improve the ability to translate findings in animal and human models of MND into the clinic. It is hoped APRALS can provide a rich pipeline of promising treatment candidates for clinical trials applicable to the majority of people living with MND.

The recipients of the Daniel McLoone Major Research Initiative are jointly funded by MND Research Australia (MNDRA) and FightMND.

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 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 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 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 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: 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.