MND Australia

MND Research Australia grants awarded 2021

Download 'MNDRA Funded Research 2021'

MND Research Australia has awarded almost $3 million to support the best MND research commencing in 2021. MNDRA is indebted to the generosity of donors, the MND & ME and MonSTaR foundations and the State MND Associations who fund this research.

The suite of grants awarded at the annual grants allocation meeting on 13 November 2020 comprises the Betty and John Laidlaw MND Research Prize for a mid-career researcher, three postdoctoral fellowships, 14 innovator grants and 8 bridge-funding grants. Two PhD Scholarship Top-Up grants were awarded in early 2021.

Research Fellowships

Lead investigator: Associate Professor Yazi Ke
Institution: Macquarie University 
Title: Novel therapeutic strategies targeting TDP-43 in Motor Neuron Disease

Our research team has discovered a new, previously unidentified protein complex that appears to be involved in Motor Neurone Disease (MND). This protein complex contributes to disease processes such as nerve cell death. This proposal has three main aims: firstly, to understand how different components of this protein complex contribute to its function; secondly, to study this protein complex in an established MND mouse model to understand its disease-relevance; and, finally, to harness the knowledge of this protein complex in the development of two highly feasible therapeutic approaches in a pre-clinical setting. This project could identify new therapies for 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 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 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.

Innovator Grants

Lead investigator: Dr Shyuan Ngo
Institution: University of Queensland, QLD
Title: MND in space and time: deciphering the spatio-temporal landscape of cell-autonomous and non-cell-autonomous drivers of motor neuron death in MND

Motor neurons are usually supported by a number of different cells that sustain their function and survival. In MND, it is proposed that these support cells become toxic and contribute to the death of neurons, although we do not know how this occurs. Using mini 3D spinal cords that we have generated from MND patient skin cells, we will study how neurons and their support cells interact over time. This will allow us to generate the first “cell-to-cell communication network maps” that will give us insights into how we can manipulate this communication to save neurons from death.

Lead investigator: Dr Robert Henderson
Institution: University of Queensland, QLD
Title: A Novel PET Imaging Marker of Astrocytes and Glutamate Reuptake in Brain and Spinal Cord in ALS

Damage to motor nerves through activation (“excitotoxicity”) is long-recognised as a potential avenue to target new therapeutics in MND. To date, there has been no reliable method to image excitotoxic injury in vivo. This novel project will test a new PET imaging method to identify key alterations in the main transporter of glutamate, the principal excitatory neurotransmitter, into glial cells in the brain and spinal cord of patients with MND. The ultimate objective is that this method will help to predict progression in individual MND patients and aid in the selection of new therapies for clinical trials.
 

Lead investigator: Dr Colin Mahoney
Institution: University of Sydney, NSW
Title: Establishing the role of high definition-density EEG in the diagnosis and monitoring of MND

There continues to be significant challenges in diagnosing and successfully treating those with motor neuron disease. We increasingly recognise that MND is a multi-systems disease, affecting structures beyond the motor systems, often in advance of weakness. It is crucial to develop sensitive tools to detect pathological changes across other brain regions. We will use high-density electroencephalography (EEG), to assess abnormal brain wave changes relating to both cognitive and motor processes, potentially in advance of motor weakness. The detection of early brain changes using this innovative technology may reduce diagnostic delay, and improve precision in prognosis and enrolment in clinical trials.
 

Lead investigator: Dr David McKenzie
Institution: University of Sydney, NSW
Title: Development of an amperometric biosensor for the detection of TARDNA binding protein 43 (TDP-43) in MND

The underlying causes of amyotrophic lateral sclerosis (ALS, a subtype of MND) are not yet completely understood. This complicates timely and accurate diagnosis and the development of new efficient treatments. The hallmark of ALS is a protein named TDP-43 that accumulates in degenerating motor neurons of around 95% of people with ALS. We will develop a biosensor, a device that is able to detect TDP-43 in liquids, to study in future why and how this happens and if it can be reversed. In future, our biosensor can also be modified to detect other molecules relevant for ALS or other MNDs.
 

Lead investigator: Dr Adam Walker
Institution: University of Queensland, QLD
Title: Defining the involvement of ubiquilin-2 in MND

The mechanisms that cause the death of motor neurons in MND are still not completely understood. In this project, we will employ cutting-edge genetic engineering technology in cells to identify genes that control the pathology formed by a key MND-related protein. Importantly, unique inherited mutations in this core pathological protein also cause MND in some Australian/New Zealand families. We will analyse the mechanisms of disease related to this protein, and compare our results to human pathology. Overall, these studies will define, in an unbiased high-throughput manner, the early pathological mechanisms involved in MND.
 

Lead investigator: Dr Mouna Haidar
Institution: The Florey Institute of Neuroscience and Mental Health, VIC
Title: Will reducing abnormal cortical activity in MND have a therapeutic effect?

Nerve cells in the motor regions (or motor neurons) of the brain carry signals to the spinal cord which in turn communicate with muscles to control movement. These brain motor neurons are overactive early in MND and eventually die, losing their ability to initiate and control muscle movement. We will evaluate a novel genetic approach targeted to brain motor neurons to reduce their overactivity in a mouse model of MND. Our approach uses "chemogenetic technology" to selectively reduce the overactivity of brain motor neurons. This study will encourage future use of our novel approach for the potential treatment of MND.
 

Lead investigator: Dr Nirma Perera
Institution: The Florey Institute of Neuroscience and Mental Health, VIC
Title: 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.
 

Lead investigator: Dr Victor Anggono
Institution: University of Queensland
Title: Molecular mechanisms underlying the cytoplasmic aggregation of the RNA binding protein, SFPQ, in ALS

The mislocalisation and aggregation of RNA binding proteins are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms underlying these aberrant processes are poorly understood. This project aims to define the molecular basis of zinc-induced cytoplasmic aggregation of an ALS-associated RNA binding protein, SFPQ. Using a combination of biochemistry, and structural and cell biology, this project will examine how two human SFPQ variants that are exclusively found in familial ALS subjects affect neuronal functions. The outcomes of this study will provide a novel conceptual framework for understanding the cytoplasmic aggregation of RNA binding proteins in ALS.
 

Lead investigator: Professor David Berlowitz
Institution: University of Melbourne
Title: REPAIR MND: REduced PAtient – ventilator asynchrony with Artificial Intelligence assisted Respiration in MND

Non-invasive ventilation (NIV), overnight breathing support with a machine and mask, is the most effective way to increase survival in MND. NIV only works if you use it and our team has shown that careful coordination of the breathing machine to the patient can convert NIV non-users into users. The coordination process is however very labour intensive and therefore challenging to translate into clinical practice. This project will build an Artificial Intelligence-based decision support tool (REPAIR MND) that will increase clinicians’ capacity to optimize NIV and usage; 20% more people with better usage is 20% more people surviving longer.
 

Lead investigator: Dr Frederik Steyn
Institution: University of Queensland, QLD
Title: Targeting NAT1 to improve metabolism and slow disease progression in MND

Through working with people with ALS we have made new discoveries on a mechanism that could contribute to more rapidly progressing disease, and impairments in metabolism that are associated with rapidly progressing disease. NAT1 is an ancient protein that controls how our mitochondria respond to metabolic stress. We have found that NAT1 is linked to metabolic imbalance and faster disease progression in people with ALS. We will now conduct a world first study to understand how NAT1 modifies the body’s response to ALS. This will help reveal how we might target NAT1 to improve outcomes in ALS.
 

Lead investigator: Professor Ian Blair
Institution: Macquarie University, NSW
Title: Genome-wide detection of short tandem repeats that are expanded in ALS

DNA mutations are responsible for familial MND and genetic factors contribute about half the risk of developing sporadic MND. However, the genetic causes of MND are unknown in one third of MND families and most genetic risk factors are unknown. Rare expansions of DNA repeat sequences cause many other neurodegenerative diseases. Until recently we had little capacity to screen MND patients for these repeated sequences. Excitingly, this is about to change: drawing on latest technologies and bioinformatics tools, this project will screen Australian MND patients in combination with international datasets to make fresh inroads to solving the genetic basis of MND.

Lead investigator: Dr Christopher Bye
Institution: The Florey Institute of Neuroscience and Mental Health, VIC
Title: Next generation pre-clinical modelling for MND

Using a small skin sample from a person with MND, we can now grow motor neurons identical to those inside of that person’s body. This is an important breakthrough because we can use these motor neurons to find and test drugs to treat MND in that person. In this project, we have developed a new approach to grow these motor neurons inside a “living brain” to more accurately test potential treatments. We aim to show that this “living brain” model can accelerate the selection of drugs for clinical trials for people with MND.
 

Lead investigator: Professor Pam McCombe
Institution: University of Queensland, QLD
Title: Revisiting excitotoxicity in ALS: how does this occur?

In MND, some of the damage to motor neurones comes about because of over-excitation. This appears to be an early event in disease. This study will examine how this occurs. We have developed novel techniques to measure amino acids that can cause over-excitation and will determine whether these are elevated in the blood of MND patients. In addition, our preliminary studies have discovered a novel molecule that helps reduce over-excitation. We will use genetic techniques to see whether variation on this molecule is associated with the clinical course of MND. This would be evidence of its involvement in MND pathogenesis.
 

Lead investigator: A/Prof Bradley Turner
Institute: The Florey Institute of Neuroscience and Mental Health, VIC
Title: Defining upper motor neuron markers using translational RNA profiling

There is increasing evidence that MND pathology originates from the brain and spreads to the spinal cord. Yet, the molecular makeup of motor neurons in the brain is poorly understood in MND. To unravel the mechanisms behind brain dysfunction in MND, specific molecular markers or 'sign posts' of brain motor neurons are urgently needed. This project will combine next-generation genetic sequencing technology with new genetically engineered mice to define the molecular makeup of brain motor neurons for the first time. Identifying molecules that are both specific and unique to brain motor neurons will vastly accelerate research in MND, allowing us to understand the mechanisms underlying their vulnerability to degeneration in MND and highlight pathways to potential effective treatment.
 

Professor Julie Atkin, Macquarie University, NSW
Novel mechanisms of neurodegeneration induced by dysfunctional actin dynamics in MND

Dr Richard Gordon, University of Queensland, QLD     
Targeting inflammasome-driven neuropathology and motor neuron death in MND using a clinically approved cancer drug

Dr Albert Lee, Macquarie University, NSW    
Clearance of TDP-43 by PROteolysis TArgeting Chimera (PROTAC) dual targeting to treat ALS

Dr Nicole Fewings, University of Sydney, NSW    
Natural Killer cells in amyotrophic lateral sclerosis

Dr Marco Morsch, Macquarie University, NSW    
The unexplored posttranslational modification (SUMOylation) of TDP-43 affects aggregate formation and localisation

A/Prof Mary-Louise Rodgers, Flinders University, SA    
Urinary Neopterin as a candidate biomarker that can be used to test disease progress in clinical trials for Motor Neurone Disease

Dr Kara Vine, University of Wollongong, NSW    
Non-invasive drug delivery across the blood brain barrier: Improving the bioavailability of drugs for MND

Dr Trent Woodruff, University of Queensland, QLD    
Transcriptomic and Functional Evaluation of Immune-Activated Monocytes in MND
 

MNDRA PhD Scholarship Top-up Grants

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: Courtney Clark
Institution: University of Tasmania
Title: Inhibitory Regulation of Motor Neurons: A new target mechanisms for MND

Currently there are few treatments available to motor neuron disease patients, which provide substantial improvement in lifespan and quality of life. Previously therapies have focused on improving motor neuron pathology. However, in amyotrophic lateral sclerosis (ALS), inhibitory network activity which is vital for supporting motor neuron function is dysfunctional. Through the use of mouse models and induced-motor neurons, interneurons and glia derived from patient cells, this project aims to understand how inhibitory interneurons can be used as a therapy to improve motor neuron health in ALS.

 

Lead investigator: Laura Reale
Institution: University of Tasmania
Title: Can we stop the spread of TDP-43 pathology in ALS?

ALS is caused by a destruction of neurons that are part of the motor system in the brain and spinal cord. It is not known how disease moves through this system and we have few effective treatments to stop the spread. In my PhD, I aim to discover why one population of neurons can make another population stop working, ie, how the disease spreads, and test a non-invasive intervention to stop this destruction from spreading. If we can better understand why the whole system fails and how to protect against this, then we can develop new effective treatments for ALS.

Lead Investigator: Megan Dubowsky
Institution: Flinders University
Title: Endogenous retroviruses as a cause of motor neurone disease

Anti-retroviral treatment given to MND patients in the Lighthouse trial has suggested that endogenous retroviral expression may be a cause of MND. This PhD project aims to define a link between endogenous retrovirus and MND pathology. MND patient-derived stem cells will first be examined for evidence of endogenous retroviral activity and for the associations between TDP-43 pathology and inflammatory signals. The TDP-43 mouse model of MND will be used to determine effectiveness of antiretrovirals in decreasing the disease-associated protein, TDP-43. If successful, this project would demonstrate how endogenous retrovirus can be a potential therapeutic target for MND, through the use of antiretrovirals.

 

Lead Investigator: Marcus Dyer
Institution: University of Tasmania
Title: Neuronal excitability in ALS – a focus on TDP-43 mislocalisation

In the vast majority of ALS cases, pathological movement of a protein, TDP-43, from the cell nucleus into the outer parts of the cell occurs. The pathological mechanism of how mislocalised TDP-43 causes motor neuron death is not known. This PhD project hypothesises that the presence of TDP-43 in the cytoplasm affects the activity of neurons, eventually causing their death. The project will identify if alterations in activity are one of the earliest changes as a consequence of TDP-43 misprocessing, and if we can potentially prevent this pathogenic mechanism from driving the onset and progression of ALS. 

Currently funded multiyear grants from previous years

Lead investigator: Dr Shyuan Ngo
Institution: University of Queensland, QLD
Title: From the nucleus to the powerhouse: investigating how TDP-43- mitochondrial interactions wreak havoc in MND

In MND, the TDP-43 protein forms clumps inside neurons. While we know that these clumps of TDP-43 are toxic to the cell, we don’t know how this leads to neuronal death. We will use neurons made from human skin cells to study whether interactions between TDP-43 and mitochondria (the powerhouse of the cell) causes a breakdown in the mitochondrial network, and an inability of mitochondria to function properly, ultimately leading to the death of neurons. This will allow us to identify a key cause for the death of neurons in MND; a critical step towards developing treatments.
 

Lead investigator: Dr Mehdi van den Bos
Institution: Westmead Hospital, NSW
Title: Deep learning as a tool to advance the diagnosis and pathophysiological understanding of ALS

ALS can be a difficult disease to diagnose and is proving even more challenging to cure. Increasingly we are realising that early intervention is needed and there are many signs brain overactivity is an early driving cause of the disease. This fellowship proposes to use advanced neurophysiological methods (probing brain function with magnetic brain stimulation and brain wave recordings) together with artificial intelligence (the technique of deep learning) to make possible early diagnosis, improve our understanding of the drivers of the disease in patients and find a reliable biological marker to accelerate drug trials that will deliver a cure.
 

Lead investigator: Dr Luke McAlary
Institution: University of Wollongong, NSW
Title: Targeting Prion-Like Strains of TDP-43

Toxic proteins in MND are capable of spreading from cell to cell in the spinal cord and brain by recruiting normal healthy protein. This spread is controlled by the shape of the toxic protein, some shapes spread more readily than others. Advanced imaging technologies have been produced where we can see the shape of individual proteins. We plan to use these imaging technologies to define the shape(s) of toxic MND proteins and apply a broad set of drug discovery methods to identify the best drugs to target them.
 

Lead investigator: Dr James Hilton
Institution: University of Melbourne
Title: Ferroxidase dysfunction drives glial ferroptotic stress and motor neurone death via neurotoxic A1 astrocyte conversion

Proper supply and regulation of copper and iron is essential for biological functioning. Adverse impacts on these processes cause their availability to become compromised in some circumstances and accumulate to pathological levels in others. We have found this copperiron axis is dysfunctional in the human MND central nervous system and has downstream pathological implications.  This project aims to better understand this pathway and examine how a dysfunctional copper-iron axis can lead to motor neurone death. We anticipate that elucidating the underlying mechanisms will identify new opportunities across different points of the malfunctioning pathway for developing new therapeutic interventions.

Lead Investigator: Dr Rosemary Clark
Institution: University of Tasmania
Title: Clinical heterogeneity in ALS: insights from interneurons?

The function of neural circuits and networks can be controlled, in part, by inhibition exerted by the interneurons. In amyotrophic lateral sclerosis (ALS), inhibitory network activities that support motor function can be altered before symptoms manifest and interneurons are implicated, however, how this relates to clinical characteristics is unclear. Through the use of novel mouse models, induced-interneurons derived from patient cells and careful examination of the ALS brain, this study will determine if specific interneuron pathology contributes to variable clinical phenotypes. This will be essential for understanding if motor alteration can be restored by improving the function of interneurons.