To Investigate The Role Of ATM Protein In Protecting Against Neurodegeneration
Funder
National Health and Medical Research Council
Funding Amount
$953,662.00
Summary
The overall aim of the project is to employ a rat model to investigate neurodegeneration in patients with ataxia-telangiectasia (A-T). Ataxia-telangiectasia is a complex multisystem disorder characterised by progressive neurological impairment, variable immunodeficiency and cancer predisposition. The rat model recapitulates the neurodegeneration in patients and thus this project will provide important insight into the nature of the defect as well as approaches for the treatment of the disorder.
Development Of Iron Chelators For The Treatment Of Friedreichs Ataxia And The Role Of Frataxin In Iron Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$550,987.00
Summary
Friedreich's ataxia (FA) is a neuro- and cardio-degenerative disease where there is an accumulation of toxic Fe in the mitochondrion. Excitingly, work from our current NHMRC grant showed iron plays a significant role in FA pathology. Importantly, we developed new drugs (Fe chelators) which rescue the cardiac pathology of FA in an animal model. Studies will now assess if our drugs prevent the neurodegeneration of FA in another animal model. This work could lead to novel therapies for FA.
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$606,000.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that c ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that cause severe damage. Further, cells deficient in frataxin are sensitive to oxidant stress and Fe chelators rescue oxidant-mediated death of cells from FA patients. Indeed, free radical scavengers have shown to be of use in the treatment of this disease. Studies in DR's lab during this NHMRC grant have shown that frataxin is down-regulated by erythroid differentiation or the haem precursor, protoporphyrin IX (BLOOD 2002;99:3813-22). These data indicate a role for frataxin in Fe metabolism and the pathogenesis of FA. In this study we will continue to examine the role of frataxin in the way cells handle Fe using experimental models developed under the current NHMRC grant. These include transfected cell lines with low frataxin expression generated using an expression vector containing anti-sense frataxin cDNA. Further we obtained the frataxin conditional KO mouse and generated a breeding colony. These animals display many of the pathological features of FA and are the best current model of the disease. Indeed, they will be critical for assessing the role of frataxin in Fe metabolism and as a model to test the ability of Fe-binding drugs to prevent the pathology observed. We designed lipid-soluble chelators that can enter the mitochondrion to bind Fe (Biochim Biophys Acta 2001;1536:133-140) and these ligands will be tested to prevent disease progression in the KO mice. This exciting research is crucial for understanding the pathogenesis of FA and in creating new therapies.Read moreRead less
Pathogenic Repeat Expansions In Ataxia: Advancing Gene Discovery And Genetic Diagnosis
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Hereditary ataxia is a severe neurological disorder that results in impaired coordination and balance and affects 1 in 20,000 Australians. Ataxias are often caused by complex genetic mutations called repeat expansions (RE), which are difficult to detect. Therefore, genetic diagnosis of ataxia remains limited and poorly accessible, leading to a gap in clinical care. In this study, we will utilise modern advances in genetic sequencing technology to diagnose and discover ataxias caused by REs.
Dissecting The Pathogenesis Of The Severe Neurodegenerative Disease, Friedreich’s Ataxia: Development Of Novel Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
Friedreich’s ataxia is a devastating neuro- and cardio-degenerative disorder which does not have an effective cure. The studies proposed in this Fellowship are crucial for understanding the progression of this disorder and the development of excitingly new therapeutics.
Improving Upper Limb Function In Hereditary Cerebellar Ataxia
Funder
National Health and Medical Research Council
Funding Amount
$437,034.00
Summary
Friedreich ataxia (FRDA) causes in-coordination and muscle weakness which may result in the affected person being unable to walk or use their arms effectively. In-coordination is a result of destruction of nerves in the spine and the area of the brain that controls movement (cerebellum). This study will assess the use of brain stimulation to improve coordination and function in people with FRDA. The results of this study may also result in treatments for similar inherited cerebellar ataxias.
Communication And Swallowing Outcomes In Patients With Acquired And Progressive Neurological Disorders
Funder
National Health and Medical Research Council
Funding Amount
$426,556.00
Summary
We all talk, eat and drink, but it’s not until we lose these skills that we recognise their importance. Communication & swallowing disorders following from progressive brain disorders such as dementia and ataxia result in daily disadvantage through poor educational and employment outcomes & social isolation. These deficits make the evaluation, long term monitoring and treatment a critical element in disease management.
INVESTIGATING PROPRIOCEPTION AND SENSORIMOTOR CONTROL IN HUMANS DEVOID OF FUNCTIONAL MUSCLE SPINDLES
Funder
National Health and Medical Research Council
Funding Amount
$335,983.00
Summary
Specific genetic mutations can lead to widespread changes in the body. Here we are looking at congenital Hereditary and Sensory Autonomic Neuropathy type III (HSAN III). Affected individuals have difficulty walking, which progressively worsens over time. This series of experiments aims to increase our understanding of the underlying neurophysiological disturbances in HSAN III.