Susie Harris Memorial Fund Grant
Dr Julie Atkin
MND Research Group, La Trobe University,
Victoria
Failure of
ER-Golgi
trafficking
as a
central
mechanism
of
toxicity
in motor neuron disease.
The diverse
forms
of
MND
all
have
similar
symptoms
and
pathology.
Despite
many
studies
into
possible
molecular
mechanisms
underlying
neurodegeneration,
definition
of
the primary
mechanism
still remains
elusive.
We
have
exciting
new evidence
that
the
death
of
motor
neurons
occurs
by the
same
basic
cellular
processes
in different
forms
of MND.
This
proposal
aims
to
identify
the
initial
trigger
of
these
common
disease
mechanisms
in
MND.
Understanding
these
processes will
enable
the development
of
more
effective
therapies
in
the
future.
Peter Stearne Grant for Familial MND
Dr Ian Blair
Northcott Laboratory, ANZAC Research Institute, NSW.
Identifying and establishing the role of new MND genes in familial and
sporadic cases.
The
only proven causes of MND are gene mutations that lead to motor neuron
death. The fact that more than one MND gene has been identified to-date
suggests that the disease involves multiple biological mechanisms.
These mechanisms remain elusive, with most genes yet to be identified.
Our preliminary studies indicate that we have identified mutations in
new familial MND genes. The aim of this proposal is to determine the
broader contribution of these genes to MND and the role of the
mutations. Each new gene offers a unique opportunity to discover the
mechanism leading to MND. Any new MND gene or protein will potentially
be a new therapeutic target. It will also add to existing genetic
testing regimes (MND diagnostic laboratories, including ours, currently
test SOD1, TDP-43 and FUS in MND but these only account for about 2% of
cases) and be available for the development of tests for use in
prognosis and in monitoring drug trials in mice and ultimately in
clinical trials.
Mick Rodger Benalla MND Research Grant
Dr Tim
Karl
Neuroscience Research Australia, NSW
A novel
mouse model for motor neuron disease.
Motor
neuron disease (MND, also known as amyotrophic
lateral sclerosis, ALS) is a devastating neurodegenerative
disorder caused by death of the nerve cells controlling the voluntary
muscles. MND patients experience a series of emerging symptoms
including progressive limb muscle weakness, speech and swallowing
difficulty and eventually respiratory failure. The disease is often
fatal within 2-5 years of diagnosis. The majority of MND patient are
sporadic, but approximately 10% of the patients have a family history.
The mechanism underlying MND is unknown. Some environmental factors,
such as prolonged exposure to neurotoxins and head injuries, have been
proposed. To date, gene mutations are the only proven causes.
The
protein TDP-43 was identified as a major component of the protein
clusters found in MND patient brains and spinal cords. Blair and
colleagues found several mutations in the TDP-43 gene from both
sporadic and familial MND patients. However, it remains unclear how
these mutations cause MND. Current studies suggest that these mutations
may cause the protein TDP-43 to become toxic. Our preliminary results
suggest that introducing these mutations into nerve cells reproduces
features seen in MND patients. Mutated TDP-43 caused more nerve
cell death than the normal TDP-43 gene. We are now proposing to
investigate the neuro-behavioural effects of one of the mutations (i.e.
TDP-43M337V) in mice. This will enhance our knowledge
regarding TDP-43 function and its role in MND and answer the question
why the mutation leads to selective toxicity in motor nerves.
Importantly, these mice can serve as a model for the development of
diagnostic tools and treatments.
Charles and Shirley
Graham MND Research Grant
Dr
Pamela McCombe
The
University of Queensland Centre for Clinical Research
MND:
not a simple disease.
Patients with motor neurone disease vary in their clinical features,
such as the site of onset of weakness and whether they have
predominantly mixed or upper or lower motor neurone signs, and in the
rate of progression of disease and in their length of survival. We have
developed precise measures of the rate of loss of upper and lower motor
neurones, as well as blood biomarkers of neuronal death. We will use
these techniques to look in detail at a group of subjects with MND, to
look at the relationship between loss of upper and lower motor neurones,
the pattern of spread of disease from one site to another and factors
such as the immune response and gender that could influence the rate of
progression of disease.
MND Victoria Research Grant
Dr
Eneida Mioshi
Neuroscience Research Australia, NSW
Cognitive and behavioural changes in MND: relation to clinical
phenotypes and impact on carer burden.
MND was
described as a pure motor syndrome in the past. More recently, studies
have shown that unfortunately this is not the case, with a great
proportion of patients developing also cognitive (such as memory,
judgement and problem solving) and behavioural (such as apahty, which is
a type of lack of motivation not related to depression) problems. These
cognitive and behavioural changes seem to relate to worse prognosis, and
the combination of these changes and physical disability compound to
high levels of burden for carers. We aim to investigate which MND
presentations (limb or bulbar) are likely to cause changes in cognition
and behaviour, which will help health professionals in making accurate
prognosis and deliver tailored care. We also aim to investigate the
underlying changes in the brain behind these deficits, which could be
addressed in drug treatments in the future. Finally, we will study the
contributions of physical, cognitive and behavioural changes to carer
burden, in order to identify the main factors behind burden and address
them adequately in services, websites and informative leaflets.
Graham Smith MND Research Grant
Professor Garth Nicholson
ANZAC
Research Institute, University of Sydney
Sporadic MND: the contribution of genes, biomarkers & metabolites
Finding
the cause of the common sporadic form of MND is proving extremely
difficult. Association studies involving thousands of sporadic cases
has not found a cause. However the study of MND families has been
fruitful as a number of genes have been implicated and various
mechanisms causing the death of MND neurones have been found. The
relevance of familial MND gene variations to sporadic MND now has to be
determined. Most of these gene variants cause only a small proportion
of sporadic MND. We propose that sporadic MND has many causes made up
of particular gene variations which when strong cause rare familial
cases and when weak, cause sporadic cases. This application aims to
find whether new gene variations that cause familial MND also cause
sporadic MND. To do this we wish to collect sporadic MND samples and
test them for gene variations found in families with MND. The project
will also collect plasma samples to study the BMAA toxin and kynurenin
pathway toxic catabolites in collaboration with MND researchers at the
University of NSW and the University of Technology. This work aims to
continue the collection of vital blood samples for future research from
sporadic motor neurone patients, commenced by Associate Professor Roger
Pamphlett’s DNA bank which ceased sample collection this year.
Roth Foundation MND
Research Grant
Dr Mary-Louise
Rogers & Prof Robert Rush
Human
Physiology, School of Medicine, Flinders University SA
Improving targeted down-regulation of SOD1G93A in MND mice.
Motor
Neuron Disease (MND) is an illness of nerves controlling muscles, which
results in a creeping paralysis and death; there is no effective
treatment. We have developed a technology called immunogenes to enable
antibodies to deliver genes into nerves. We have also found that an
antibody can increase the life span of the transgenic mouse that models
MND. The project combines this novel antibody and our immunogene
technology to test the agent as a potential drug for the treatment of
MND in mice. Successful outcomes will encourage development of targeted
treatments for MND in humans.
Mick Rodger Benalla MND Research Grant
Dr Bradley Turner
Florey Neuroscience
Institutes, University of Melbourne
Exploring the therapeutic potential of survival motor neuron
protein for MND
Survival motor neuron (SMN) is an essential protein required by motor
neurons and its loss causes the childhood disease SMA. We recently
showed that SMN levels were low in laboratory models of MND and patients
with MND. Treatment of MND mice with SMN was shown to prevent motor
neuron loss, suggesting that SMN could have a protective role in MND.
We now wish to determine whether SMN is also effective in different
animal models of MND looking at nerve injury and newly available TDP-43
mice. These studies will help confirm whether SMN should be considered
an important player in MND and a potential target of interest for
treatment approaches.
Connie's Step Forward for MND Research Grant
Assoc Prof Steve Vucic
Westmead Millennium Institute, University of Sydney
T
cells: a vehicle for neuroprotection in ALS?
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal,
neurodegenerative disease with most affected patients dying of
respiratory compromise and pneumonia after 2 to 3 years; although
occasionally individuals may survive for many years. Recently,
purification and injection of a specific type of immune cell was shown
to delay disease onset and slow progression in an animal model of ALS.
Moreover this cell type appears to be dysregulated in human ALS.
These findings open up a new and exciting direction for potential
treatment of ALS. The goals of this study are to determine how the
function of these immune cells relates to human ALS and its progression;
and to determine whether a recently described treatment that boosts this
cell type can delay disease progression in the animal model of ALS.
Zo-eč MND Research Grant
Dr
Robyn Wallace
Queensland Brain Institute
Analysis of TDP-43 target genes in C. elegans
Protein
tangles that aggregate in affected nerve cells are a pathological
hallmark of MND. Studies of MND patient cells have demonstrated that
TDP-43 protein is a principal component of these nerve cell aggregates.
Genetic mutations associated with MND have also been identified in the
TDP-43 gene. However, the role of TDP-43 in the pathogenesis of MND
remains unclear. TDP-43 is involved in gene regulation and we have
recently identified a number of genes that bind to TDP-43. The aim of
this project is to study the genes that are regulated by the TDP-43
protein in a living organism. The nematode worm is widely used in
neuroscience research because its well-characterised and less complex
nervous system facilitates rapid analysis of nerve cell function. The
nematode will be used to analysis the role of TDP-43 target genes in
motor neuron function. These studies will improve our understanding of
how abnormal TDP-43 causes MND and highlight cell processes that could
be targetted for the future development of new therapies.
Terry Quinn MND Research Grant
Dr Anthony White
Dept of Pathology,
University of Melbourne, Victoria
Targeting kinases to control TDP-43 and FUS accumulation in
motor neuron disease.
Motor
neuron disease (MND) or amyotrophic lateral sclerosis (ALS), is a
group of fatal adult-onset illnesses in which the function of motor
neurons in the spinal cord and brain progressively deteriorates leading
to death in 1-5 years. Little is known about the cause of MND and there
are no effective long term treatments. Recently, the RNA-binding
proteins known as TDP-43 and FUS have been found to cause most cases of
genetic MND and are likely to have a critical role in sporadic cases.
In brain and spinal cord of MND patients, these proteins leave their
normal location in the nucleus and accumulate in the cytoplasm causing
neuronal cell death. However, there is little understanding of how this
abnormal process occurs. Recently, using new cell culture models
generated through generous support from the MNDRIA we have been able to
recapitulate these processing changes in neuronal cells. Our key
finding has been that cell signaling kinases such as JNK and ERK have a
critical role in controlling cytosolic accumulation, abnormal processing
and aggregation of TDP-43 (initial steps in neuronal death). In the
present study, we will investigate how activation of key cell signaling
kinase pathways control cytosolic accumulation and toxicity of both
TDP-43 and FUS in neurons and identify novel targets for inhibition of
abnormal protein accumulation using kinase inhibitors. These studies
will open up a completely novel area of therapeutic treatment for MND
and related neurological diseases.
Rosalind Nicholson MND Research Grant
Professor Mark Wilson
University of Wollongong
Protein
aggregation and chaperones: key players in MND
The
motor neurone disease amyotrophic lateral sclerosis (ALS, hereafter
simply referred to as MND) is a currently untreatable disease that
attacks nerves controlling voluntary muscles. It usually occurs in
adults and has an appalling prognosis, commonly leading to loss of
muscle control and rapid death within a few years of onset. Current
evidence strongly suggests that inappropriate aggregation of protein
molecules is a primary contributor to MND pathology, however there is
very limited understanding of the molecular processes involved and the
role of chaperones (the usual defence against protein aggregation).
This current application forms a part of a larger project (pending
Project grant application 1022564 currently under review at the NHMRC),
and will (i) identify and quantify proteins in the insoluble protein
deposits found in human MND spinal cord tissues, thereby identifying new
genes important in MND, and (ii) screen the effects of a range of
chaperones on the aggregation and toxicity of TDP-43 (one of the
proteins already known to be present in MND deposits and implicated in
causing disease), both in vitro and in cell models. The larger
project will also screen the effects of these chaperones in transgenic
Drosophila (fruit fly) expressing TDP-43, where we have already
shown that expression of a chaperone can protect against loss of
locomotor activity and extend life. The new knowledge this project
generates will be critical for the future development of new diagnostics
and effective therapies for MND.
Dr
Catherine Blizzard
Menzies Research
Institute, University of Tasmania
Bill Gole Postdoctoral
Fellowship for MND Research 2011 - 2013
Investigating the cause of site-specific excitotoxicity in ALS.
Motor neuron disease is
caused by a loss of function of the nerve cells controlling the
muscles. This loss of function of the nerve cells may be due to over
excitation of nerve cells, either at the muscle or at the site of the
nerve cell bodies, the spinal cord. I aim to explore these two
possibilities on the toxic site leading to nerve cell degeneration.
This will enable the role that over excitation of the nerve cells could
play in the disease progression to be determined.
Dr
Rachael Duff
Western Australian
Institute for Medical Research
Bill Gole Postdoctoral
Fellowship for MND Research 2011 - 2013
The application of new generation genetic
techniques to motor neuron disease.
The majority of MND
patients have sporadic disease of unknown cause. However, for
approximately 10% of patients, MND runs in families. A number of genes
causing this inherited MND have been identified, but for the majority of
patients with inherited MND the causative gene is unknown. In this
project I aim to find the disease gene in MND families where it has not
been identified. I aim to use new genetic technology only available in
the last few months. I also aim to investigate genetic factors
controlling which family members do or don’t get familial MND and to
investigate genetic susceptibility in sporadic MND. This research will
allow accurate diagnosis and family planning for families with inherited
MND, improve our understanding of the way the genes result in disease,
and this will in turn provide information about possible routes to
treatment for MND.
Dr Shu Yang
Northcott Laboratory, ANZAC Research Institute, NSW.
Bill Gole Postdoctoral
Fellowship for MND Research 2010 - 2012
Investigating the role of recently identified mutant genes in MND
pathogenesis.
The disease mechanism
underlying motor neuron disease (MND) is currently poorly understood,
making the development of diagnostic tools and therapeutics difficult.
However, proteins that play fundamental roles in MND pathogenesis have
recently been identified, providing new hope for understanding the cause
of MND and development of therapeutic and diagnostic tools. The 43 kDa
TAR DNA binding protein (TDP-43) was recently identified as a signature
component of the abnormal protein aggregates found in the brain and
spinal cord of most sporadic and familial MND patients. Our group
identified several mutant forms of TDP-43 that appear to directly
trigger neurodegeneration leading to MND (funded by a Bill Gole
Fellowship to Dr Blair, 2006-2007). We hypothesise that identifying the
mechanisms through which rare TDP-43 mutations cause MND will be more
widely relevant to understanding the cause of familial and sporadic
MND. We will establish novel TDP-43-expressing MND cell models and a
transgenic mouse model to study the function of mutant TDP-43 protein.
The significance of
the proposed project includes a greater understanding of how
mutant TDP-43 leads to protein aggregation and motor neuron degeneration
in MND, as well as knowledge of the functions of other signature
proteins in MND, such as FUS, that may provide new diagnostic and
therapeutic targets. The establishment of the TDP-43 transgenic mouse
model may provide a better model to understand sporadic MND pathogenesis
than the existing SOD1 transgenic mouse models. This model may also act
as a useful platform for MND therapeutic development.
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 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.