Inclusion Body Proteins And Neurodegenerative Disease
Funder
National Health and Medical Research Council
Funding Amount
$389,164.00
Summary
Parkinson's disease affects 1% of people aged over 50, and a related disorder, Dementia with Lewy bodies, causes dementia in elderly patients. These diseases are characterised by inclusion bodies (Lewy bodies) in a sub population of nerve cells. Multiple system atrophy, another adult-onset neurodegenerative disorder, is also characterised by inclusion bodies (glial inclusions). Inclusions may interfere with cellular function, contributing to the process of brain degeneration. The inclusion bodie ....Parkinson's disease affects 1% of people aged over 50, and a related disorder, Dementia with Lewy bodies, causes dementia in elderly patients. These diseases are characterised by inclusion bodies (Lewy bodies) in a sub population of nerve cells. Multiple system atrophy, another adult-onset neurodegenerative disorder, is also characterised by inclusion bodies (glial inclusions). Inclusions may interfere with cellular function, contributing to the process of brain degeneration. The inclusion bodies are precipitations of proteins and other cellular chemicals. In the last 10 years, in a search for the underlying cause of these neurodegenerative disorders, there has been an intensive research effort to identify the proteins precipitated in the inclusion bodies. The present project adopts a new strategy and aims to identify the precipitated proteins in the inclusion bodies in brains of people dying with Parkinson's disease, Dementia with Lewy bodies and Multiple system atrophy. We intend to isolate the Lewy bodies and the glial inclusions from fresh brain tissue of patients dying with relevant diseases. Throughout the various steps in the isolation process, the location of the inclusion bodies will be checked with a special antibody to a particular protein (alpha synuclein) which we and others have already discovered to be present in all inclusion bodies. Proteins will then be identified using electrophoresis and amino acid sequencing. With the identification of these proteins, their role in neurodegeneration in these diseases can be examined using multiple biomedical approaches. These proteins will be important candidates for developing novel diagnostic reagents, screening for gene mutations in patients, or as the target of therapeutic intervention in these diseases.Read moreRead less
Role Of ABCA8 Transporter In Oligodendroglial Lipid Regulation And Multiple System Atrophy
Funder
National Health and Medical Research Council
Funding Amount
$651,516.00
Summary
Multiple system atrophy (MSA) is a rapid-onset brain disorder impacting on multiple functions of the body resulting in death. The cause of MSA is unknown and there is no cure. In MSA brains, the oligodendroglial cells are impaired and cannot properly make myelin (specialized lipid membrane), which is required for the proper functioning of the nerve cells in the brain. The aim of this project is to find out how changes in lipid in the brain impact on the MSA disease process.
Cancer cachexia is a devastating disease characterised by skeletal muscle wasting and weakness. It impairs patient quality of life and accounts for >20% of cancer-related deaths. My work aims to identify factors contributing to the development of cancer cachexia. This insight will then enable me to test potential strategies to prevent the wasting seen in cancer patients to improve their quality of life and to reduce mortality.
Role Of SOCS 3 In Regulating Oligodendroglial Phenotype In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$419,187.00
Summary
The response of nerve cells, known as oligodendrocytes, to an inflammatory insult dictates the severity of demyelinating diseases such as multiple sclerosis (MS). We have previously discovered that a key protein in this response is the cytokine leukaemia inhibitory factor (LIF) which, by activating the LIF receptor expressed on these cells, limits their death and reduces the clinical impact on animal models of MS. However, the therapeutic benefit of LIF is incomplete and we do not completely und ....The response of nerve cells, known as oligodendrocytes, to an inflammatory insult dictates the severity of demyelinating diseases such as multiple sclerosis (MS). We have previously discovered that a key protein in this response is the cytokine leukaemia inhibitory factor (LIF) which, by activating the LIF receptor expressed on these cells, limits their death and reduces the clinical impact on animal models of MS. However, the therapeutic benefit of LIF is incomplete and we do not completely understand the mechanisms by which LIF exerts these effects. To maximise the treatment potential of LIF we need to understand how LIF receptor signaling is modulated in the nervous system. An important protein known to regulate the activity of LIF and of other cytokines in other organs of the body is the suppressor of cytokine signaling 3 (SOCS 3) molecule. We have recently shown that the expression of SOCS 3 is increased in an animal model of MS, indicating that it is likely to modulate the activity of LIF in this context. We plan to investigate the nature of this regulation. SOCS 3 might limit the efficacy of LIF but it could also limit the deleterious effect of unbridled LIF receptor signaling. To distinguish between these possibilities, we plan to study the impact of demyelinating disease in animals in which SOCS 3 is either deleted or overexpressed in oligodendrocytes. In this way, we should be able to learn how to optimise the therapeutic potential of LIF in MS and related nervous system diseases.Read moreRead less
How Does Fampridine Affect Upper Limb Function In Multiple Sclerosis?
Funder
National Health and Medical Research Council
Funding Amount
$113,237.00
Summary
Multiple sclerosis (MS) is a common and disabling neurological disease affecting thousands of young Australians. In 2011 Fampridine received TGA approval for walking impairment in MS, but its mechanism of action is unknown and its effects on domains other than lower limb function remain untested. Our study will test whether Fampridine improves upper limb impairment in MS patients and will use electrophysiological measures of central nervous system conduction to uncover its mechanism of action.
T Cell Apoptosis In Multiple Sclerosis And Experimental Autoimmune Encephalomyelitis
Funder
National Health and Medical Research Council
Funding Amount
$299,950.00
Summary
Multiple sclerosis is a disease of the nervous system and is a common cause of disability in young adults. There is increasing evidence that multiple sclerosis is caused by repeated attacks on the nervous system by the white blood cells (lymphocytes) of the body's own immune system. A major unanswered question in multiple sclerosis is why repeated immune attacks on the nervous system occur. I have recently proposed that the repeated nature of the immune attacks in multiple sclerosis results from ....Multiple sclerosis is a disease of the nervous system and is a common cause of disability in young adults. There is increasing evidence that multiple sclerosis is caused by repeated attacks on the nervous system by the white blood cells (lymphocytes) of the body's own immune system. A major unanswered question in multiple sclerosis is why repeated immune attacks on the nervous system occur. I have recently proposed that the repeated nature of the immune attacks in multiple sclerosis results from a failure of the mechanism that switches off immune attacks on the nervous system in healthy individuals. In an animal model of multiple sclerosis we have shown that the lymphocytes attacking the nervous system rapidly commit suicide in the nervous system by a process known as apoptosis, and that this is associated with switching off of the immune attack and recovery from the disease. The present project aims to study further this process of lymphocyte suicide in experimental animals by determining whether the lymphocyte suicide is mediated through a death receptor molecule named Fas (CD95). The project will also investigate the process of lymphocyte suicide in white blood cells obtained from patients with multiple sclerosis to determine if this process is defective and to determine whether these patients have abnormalities in the Fas molecular pathway. This project will shed light on the question of why repeated immune attacks on the nervous system occur in multiple sclerosis, and has the potential to lead to the development of new treatments for multiple sclerosis.Read moreRead less