Grant-in-aid
Dr Julie Atkin
Brain Injury & Repair
Group, Howard Florey Institute, University of Melbourne
Is
Protein Disulphide Isomerase (PDI) a novel biomarker for motor neuron
disease?
There is currently no
early diagnostic test for MND and usually lengthy and detailed clinical
investigations are necessary. The evidence we obtained in earlier
studies has led us to believe that a protein called PDI may be a new and
effective biomarker of MND. In this study we will examine a large group
of MND patients in comparison to unaffected individuals, to determine
whether PDI could be used to reliably measure disease outcome and
progression, and to predict disease in patients with inherited forms of
MND. If PDI can reliably diagnose MND, this would facilitate future
studies to establish a diagnostic kit for MND or to design clinical
trials of new drugs.
Peter Stearne Grant for Familial MND
Dr Ian Blair
Northcott Laboratory, ANZAC Research Institute, NSW.
Characterisation and investigation of a new transgenic mouse model
expressing mutant TDP-43.
The only proven
causes of MND are mutations in genes that lead to death of motor
neurons. Using these mutations, mice have previously been developed
that mimic features of MND. These animals, called mouse models of MND,
have been a principal tool for testing proposed disease treatments.
Unfortunately the promise of treatments shown in existing mouse models
have largely proven unsuccessful in human trials. We recently described
mutations in a new MND gene, TDP-43. We have developed a new mouse that
carries one of these TDP-43 mutations. We now aim to monitor and test
this mouse to establish whether it develops similar symptoms to MND. If
so, this new mouse model will be available for investigating the biology
of the disease and for evaluating treatments.
Mick Rodger MND Research Grant
A/Prof Meng Inn
Chuah
Menzies Research
Institute, University of Tasmania
Effect of metallothionein and exercise on progression of motor neurone
disease.
Amyotrophic lateral
sclerosis (ALS) is the major cause of motor neurone diseases (MND),
which are progressive and ultimately fatal diseases caused by the
degeneration of motor neurons in the brain and spinal cord of patients.
Unfortunately there are no effective clinical treatments available that
can protect motor neurones from such death, with the only drug currently
available, riluzole (rilutek) conferring only a very modest alleviation
in symptoms, and is only effective over a short period of several
months. Metallothionein (MT) proteins are known to be powerfully
neuroprotective in several experimental models of neuronal injury and
disease including ALS. We now have preliminary data suggesting that
administration of MT might be effective in prolonging survival in an
animal model of ALS. This project will explore further this therapeutic
potential by assessing the possible benefits of combining MT with an
exercise regimen to improve the functional and survival outcome of a
mouse model of ALS.
Grant-in-aid
Dr Peter Crouch
Dept of Pathology,
University of Melbourne, VIC
Investigating cellular
hypoxia as a causative factor in MND and as a potential therapeutic
target.
The fundamental
biological causes of decreased motor neurone function in MND remain
unknown. Genetic clues are evident in familial forms of the disease,
but familial MND only accounts for a small minority of all cases and
these genetic clues therefore cannot explain the majority of cases.
Identifying the causes decreased motor neurone function is an essential
step in developing new and more effective therapeutics to treat MND.
The research described in this application focuses on demonstrating the
mechanism of action for a novel therapeutic compound shown to be
effective in MND model mice. Undertaking the described work presents a
unique opportunity to simultaneously progress the development of this
compound towards clinical trials, and to identify what may be an
important biological contributor to all forms of MND.
Our work to date has
shown that the copper-based compound CuII(atsm) significantly delays the
onset of MND-like symptoms in a mouse model of the disease. Most
importantly, CuII(atsm) delays the onset of paralysis in these mice.
Parallel work has started to reveal important information on how
CuII(atsm) may mediate its therapeutic effects. Essentially, we have
shown that CuII(atsm) is a relatively inert compound, but when exposed
to cells grown with inadequate oxygen supply, the CuII(atsm) becomes
activated. When activated, CuII(atsm) induces cellular responses that
have the potential to improve neuronal function. This work is highly
significant when considered in the context of current MND research, as
emerging evidence indicates that impaired cellular responses to
inadequate oxygen supply can induce development of MND.
The research
described in this application will provide information on the cellular
conditions that induce activation of CuII(atsm) and therefore generate
its therapeutic activity in MND model mice. In addition, it will
provide new information on cellular responses to oxygen supply as a
potential biological cause of MND.
Zo-eč MND Research
Grant
Dr Fiona Fisher
Neuropsychology,
Calvary Health Care Bethlehem, VIC
Emotion
recognition and social communication in MND: impact on behaviour and
carer burden.
In
recent years, there has been a surge of research into the non-motor
symptoms of MND, with the impact of MND on thinking skills, behaviour
and emotional functioning being more widely accepted. Research, while
limited at this stage, has shown that MND can damage parts of the brain
that are essential for normal understanding of emotions, and in
particular in understanding the non-verbal aspects of communication that
indicate the emotional states of others. What this means is that some
people with MND may have trouble with the finer, more subtle details of
social communication, social cognition and the ability behave
appropriately in their social interactions with other people. These
emotional processing changes have the potential to impact upon the
relationship between persons with MND and their carers.
The
proposed research project aims to investigate previously identified
social-emotional changes and investigate the relationship of such
changes with alterations in behaviour. In addition, the relationship
between social-emotions difficulties and carer burden will be explored.
This will provide new information about the frequency and impact of
emotional processing difficulties in people with MND. It will also
increase understanding of the relationship of such difficulties to
social communication, behavioural changes and carer burden.
Grant-in-aid
Dr Robert
Henderson
Dept of Neurology,
Royal Brisbane and Women's Hospital, QLD
Novel markers of motor neurone disease- quantitative upper and lower
motor neurone markers.
Motor Neurone Disease
(MND) is a relentlessly progressive disorder of upper and lower motor
neurones. Since the first description of MND in the 19th century, only
one drug (riluzole) with modest disease-modifying potency has been
developed. The diagnosis of this disorder is clinical and there is a
significant delay between the symptom onset and diagnosis, possibly
beyond the therapeutic window. Clinical signs and functional scales are
inadequate for detection or quantification of the loss of upper and
lower motor neurones. That is the reason why patient survival has been
the measure of therapeutic response in many trials. However, the
heterogeneity in the rate of progression and survival in MND patients is
challenging the outcome of clinical trials.
Our research project
focuses on novel markers that are sensitive to the progression of
disease, which might enhance the diagnostic algorithm and might be
useful to monitor the effectiveness of new therapies. We perform
neuroimaging and neurophysiology studies to identify objective upper and
lower neurone markers. In combination, these quantitative markers might
be sensitive to early therapeutic effects and might also resolve
complexities of phenotypic heterogeneity in clinical trials.
Hence, we evaluate
longitudinally patients with different clinical phenotypes of MND (e.g.
UMN or LMN predominant, pure LMN type) to quantify the rate of
progression and to understand if the degeneration of the upper and lower
segments is simultaneous, or if independent that neither is the cause or
the consequence of the other.
Grant-in-aid
Dr Qiao-Xin Li
Dept of Pathology,
University of Melbourne, VIC
Investigating the in vivo targets affected by a novel therapeutic agent
for motor neuron disease.
Motor Neuron Disease
(MND) affects the motor system required to maintain muscle control.
Inevitably the disease progresses to paralysis and premature death,
within 3-5 years after diagnosis. There are limited therapeutic options
available for treating the disease. Our current work has identified a
compound, known as CuII(atsm), that substantially delays the development
of disease symptoms in a mouse model of MND. This proposal is to
investigate the optimal treatment scheme for the CuII(atsm) before
advancing to preclinical trials, as well as the identification of in
vivo targets of CuII(atsm). Ultimately this study will help expedite the
development of effective MND therapeutic strategies.
Grant-in-aid
Dr Hakan Muyderman
Medical Biochemistry
& Human Physiology, Flinders University, SA
The
role of TDP-43 in astrocytes in motor neuron disease.
The
presence of cellular inclusion bodies links a large spectrum of
neurological diseases together, including motor neuron disease (MND).
Recently, the TAR-DNA-binding protein TDP-43 was identified as a primary
component of these inclusions and mutations in the gene encoding for
this protein have been causally linked to familiar forms of MND. However
TDP-43 positive inclusions are not only present in motor neurons but
also in surrounding glial cells, predominately in astrocytes. Although
there is no loss of these cells in MND, affected astrocytes have
pronounced changes in expression of
genes regulating essential cellular functions. In addition, in some
models of MND, sick astrocytes kill healthy motor neurons when the two
cell types are grown in culture. Based on these and similar data
it has been suggested that motor neuron cell
death could partly result from deficiencies in the interaction between
motor neurons and astrocytes. However the role of
TDP-43 in
the interplay between these two cell types is not known.
In this
context, results recently obtained in our laboratory demonstrate that
astrocytes expressing TDP-43 mutations also suffer from changes in
normal cell function. Moreover, several of these changes have the
potential to severely affect function and survival of motor neurons.
Based on these results, we hypothesise that astrocytes expressing human
TDP-43 mutations will impair normal motor neuron function and survival.
This hypothesis, which has not been tested, constitutes the overall aim
of this project. We believe that a successful
identification of astrocytic
TDP-43
protein as a component in the pathology of motor neuron disease will
present new targets for therapeutic interventions where none exists and
will aid in understanding a range of related neurodegenerative diseases.
Grant-in-aid
A/Prof Roger
Pamphlett
Stacey MND
Laboratory, University of Sydney
Looking for abnormal gene expression in ALS spinal cords using
next-generation sequencing.
Grant-in-aid
Dr Mary-Louise
Rogers & Prof Robert Rush
Dept of Human
Physiology, Flinders University SA
A
bio-marker for motor neurone disease.
Diagnosis of motor
neurone disease is usually a long, drawn out process that creates
anxiety for patients and their families. We are working to find a
bio-molecule in urine that can be used to easily diagnose motor neurone
disease. This 'biomarker' of the disease will be valuable as a way of
objectively measuring progression of the disease and also for
determining whether new drugs have value in the treatment of this
devastating illness.
Grant-in-aid
Dr Bradley Turner
Florey Neuroscience
Institutes, University of Melbourne
A
role for survival motor neuron protein in MND?
Understanding the
earliest and central pathological events in MND is essential to
developing effective treatments. We recently showed that survival motor
neuron (SMN) protein levels are lower in laboratory models of MND. SMN
deficiency occurs very early before motor neuron loss and symptoms in
MND model mice, suggesting that it may be an important mechanism for
disease. We now wish to determine whether MND patients are deficient in
SMN and whether this correlates with age of diagnosis and disease
severity. These studies will indicate whether SMN replacement may be
considered useful for MND therapy.
Charles & Shirley
Graham MND Research Grant
Dr Robyn Wallace
Queensland Brain
Institute
Identifying genes
that are affected by MND causing TDP-43 mutations.
Protein tangles that
aggregate in affected nerve cells are a pathological hallmark of MND.
Recent studies have demonstrated that TAR DNA-binding protein (TDP-43)
is a principal component of these nerve cell aggregates. This was a
major breakthrough in the understanding of MND. However, the function
of TDP-43 in the nervous system is currently unknown and its role in the
pathogenesis of MND remains unclear. Genetic mutations associated with
both familial and sporadic MND have recently been identified in TDP-43.
These mutations offer a unique opportunity to determine how abnormal
TDP-43 leads to loss of motor neurons in MND patients. The aim of this
project is to investigate how these mutations affect the normal function
of TDP-43. Specifically, we will identify genes that are regulated by
TDP-43 and determine whether these genes are altered in MND patients
with TDP-43 mutations. These studies will improve our understanding of
what causes MND and provide rational targets for new therapies.
Mick Rodger Benalla
MND Research Grant
Dr Anthony White
Dept of Pathology,
University of Melbourne, VIC
Investigating the
role of biometals in abnormal metabolism of TDP-43.
Motor neuron disease is a devastating and rapidly progressing
illness affecting adults and often results in death within 2-5 years of
diagnosis. No effective treatments or cure exists. Despite extensive
research into the underlying causes of motor neuron cell death, the
processes are still poorly understood. Recent discoveries have
identified a protein thought to have a key role in the pathways leading
to motor neuron degeneration. This protein,
TDP-43, had been shown
to undergo fragmentation into smaller pieces (called C-terminal
fragments, CTFs), followed by aggregation into clumps and are also
modified by phosphorylation and ubiquitination. This process is
believed to be associated with motor neuron degeneration. However,
little is known of the key early processes that lead to TDP-43
fragmentation and aggregation or how this results in motor neuron cell
death. We have developed a cell culture model based on use of a motor
neuron cell line to investigate factors that influence
disease-associated changes to
TDP-43. We have so far found that zinc (an important
biometal in the brain and neurodegeneration) can induce specific
TDP-43 aggregation. We are now further investigating this novel
finding and using a unique protein array-based approach to map molecular
pathways of
TDP-43-mediated motor neuron cell death. The outcomes of this project
will provide a significant advance in our understanding of TDP-43 in
motor neuron disease and may lead to development of novel treatment
approaches for patients with the disease.
Dr
James Burrell
Prince of Wales
Medical Research Institute, NSW.
PhD Scholarship
for MND Research 2009 - 2011, co-funded with NHMRC
Cognition and
behaviour in motor neuron disease.
Motor neuron disease
(MND) and fronto-temporal dementia (FTD) are fatal neurodegenerative
disorders of unknown cause. There are poorly understood clinical and
pathological overlaps between MND and FTD which this research aims to
clarify. The impact of cognitive deficits on carer burden will also be
investigated. It is hoped that this research may contribute to the
development of a pathological model that explains the development of MND
and FTD.
Dr Justin Yerbury
Centre for
Medical Biosciences,
University of Wollongong
Bill Gole Postdoctoral Fellowship
for MND Research 2009 - 2011
Probing molecular mechanisms of microglial and astrocyte
activation in ALS.
This
project combines unique expertise to perform truly pioneering studies to
determine how a genetic defect in a protein, superoxide dismutase,
affects immune processes implicated in motor neuron disease. Novel
approaches will be used to study relevant molecular interactions, both
in the test tube and in animal models. The outcomes will provide a new
understanding of these processes and may contribute towards the ultimate
development of new therapies.
Recent
research suggests that a soluble factor in ALS CSF is toxic to motor
neurones via both direct and indirect effects; the latter is
thought to involve activation of microglial cells which secrete toxic
mediators. One potential soluble factor that may promote cell
activation and neurotoxicity is extracellular mSOD1.
This
project will provide significant insights into the mechanisms by which
extracellular mSOD1 influences the development of familial ALS (fALS)
pathology. We expect that the research outcomes will
stimulate a
high level of general interest resulting in publications in high impact
international scientific journals and
provide vital clues to possible new directions for therapies to combat
fALS, for which there is currently no effective treatment.
Dr Anna King
NeuroRepair Group, Menzies Research Institute, University of Tasmania.
Bill Gole Postdoctoral Fellowship
for MND Research 2008 - 2010
Investigating the causes and consequence of axonal pathology in
amyotrophic lateral sclerosis.
Motor
neuron disease (MND) is caused by a loss of function of the nerve cells
controlling the muscles. I have recently developed a cell culture model
which mimics the degenerative changes in motor nerve cells that underlie
the onset of amyotrophic lateral sclerosis, the major cause of human
MND. I will use this model to investigate the factors and mechanisms
that cause motor neurons to degenerate, an approach which may indicate
new therapeutic opportunities for an otherwise incurable condition.
Dr Jennica Winhammar
The
Prince of Wales Medical Research Institute, NSW.
Bill Gole Postdoctoral Fellowship
for MND Research 2008 - 2010
Clinical trial to assess the neuroprotective properties
of a sodium channel blocking agent in motor neurone disease.
This
project will provide clinical trial information related to the potential neuroprotective properties of a sodium channel blocking agent in patients with motor neurone
disease. Specifically, it will establish whether the sodium channel
blocking agent can slow
disease progression. A potential therapeutic response would provide
impetus for a larger scale, multi-centre clinical trial. In addition to
providing information about potential mechanisms of neurodegeneration
and their treatment, new quantifiable measures will be further developed
to objectively monitor MND patients in a clinical trials setting.
Funding over three years is also being provided for the
MND Research Tissue Bank of Victoria (2008 - 2010)