Relationship Between Nigral Injury, Dopamine Handling And Dyskinesia In Parkinsonism
Funder
National Health and Medical Research Council
Funding Amount
$65,685.00
Summary
Parkinson's Disease is a disabling condition that results from loss of nerve cells (neurones) in the part of the brain known as the substantia nigra (SN). These neurones make dopamine. Symptoms become apparent when 80% of these neurones are gone, suggesting that compensation can occur in the brain. Dopamine can be replaced with the drug L-dopa. Unfortunately this benefit is not sustained and is frequently marred by the production of unpleasant writhing wriggling movements called dyskinesia. Thes ....Parkinson's Disease is a disabling condition that results from loss of nerve cells (neurones) in the part of the brain known as the substantia nigra (SN). These neurones make dopamine. Symptoms become apparent when 80% of these neurones are gone, suggesting that compensation can occur in the brain. Dopamine can be replaced with the drug L-dopa. Unfortunately this benefit is not sustained and is frequently marred by the production of unpleasant writhing wriggling movements called dyskinesia. These movements can also complicate the treatment for schizophrenia and other neurological conditions. The way the brain compensates for loss of SN neurones and why dyskinesia occur is unknown. However we present a hypothesis that the mechanisms for compensation also produce the dyskinesia. We have shown that an injury to the SN results in a compensatory response of vigorous sprouting of the surviving dopamine neurones. This sprouting may also explain why dyskinesias occur. The aim of this study is to establish whether the degree of compensatory response corresponds with the severity of dyskinesia and how this compensatory response can be modified or regulated.Read moreRead less
Changes In Pelvic Autonomic Neurons After Spinal Nerve Injury
Funder
National Health and Medical Research Council
Funding Amount
$176,734.00
Summary
This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic ....This project is about the effects of spinal injury on autonomic neurons that control the bladder, lower bowel and reproductive organs. One of the consequences of some types of spinal injury is that there are no signals being sent from the spinal cord to the nerve cells outside the cord, and this leads to poor bladder control, impotence, etc. We are mimicking this problem experimentally by damaging the spinal nerves that carry these signals. We have found that after this type of damage the pelvic autonomic neurons make many new connections between each other, and the types of new connections depend on which spinal nerves have been injured. This leads to the question: are these new connections good or bad? ie are they helpful in trying to get organ control back to normal or will they stop the correct connections from the spinal cord from being made in the future? This project addresses these questions by using sophisticated techniques for staining and visualising individual nerve fibres growing out from the spinal cord. We will track how well these fibres grow back and connect with the pelvic autonomic neurons. In particular, we will see whether they make correct connections, and if these connections are influenced by the new fibres that have grown between the autonomic neurons in the interim period. We will also do physiological tests to see if the new connections have the correct function. The ultimate aim of these studies is not only to understand more about regeneration, but to see what determines whether the correct connections have been made - and ideally, to give us insight into how we can make regeneration work more quickly and accurately. We believe that this work is an important adjunct to other studies on spinal injury, which mostly focuses on regaining voluntary motor control (e.g. walking); however loss of bladder, bowel and reproductive function is another important quality of life issue for spinal injury patients.Read moreRead less
Membrane Fusion In Axonal Regeneration: Molecules And Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$461,597.00
Summary
Limited nerve regeneration is the main obstacle for recovery from spinal cord and brain injuries. Understanding the cellular and molecular mechanisms underlying axonal regeneration is an essential step toward the development of novel effective therapies to enhance this process. In this proposal, we use the powerful molecular and genetic tools available for the small nematode worm C. elegans to identify and study axonal regeneration and discover the key molecules involved.
Mechanisms Of Autoantibody Mediated Axonal Injury In Inflammatory Demyelinating Neuropathies
Funder
National Health and Medical Research Council
Funding Amount
$580,197.00
Summary
Destruction of nerve fibres (axons) accompanies demyelination and may be responsible for most of the deficit in multiple sclerosis and immune neuropathies. This project will investigate the role of recently described antibodies against a normal component of the axon in axonal damage in both animal models and in patients with immune neuropathies. The project could have a major effect on approaches to management of these diseases.
After The Cloning Of The HMSNL Gene: Molecular Pathogenesis Of The Disease
Funder
National Health and Medical Research Council
Funding Amount
$258,564.00
Summary
We have completed an NHMRC-funded study, where we identified the gene for a severe disorder of the peripheral nervous system. The disease, hereditary motor and sensory neuropathy - Lom (HMSNL), presents with gait disturbances, difficulty in using the hands, muscle weakness and wasting and sensory loss. The concomitant impairment of the insulating myelin sheath surrounding nerve fibres (facilitating nerve conduction) and of the nerve fibres themselves suggests that the molecular defect lies in th ....We have completed an NHMRC-funded study, where we identified the gene for a severe disorder of the peripheral nervous system. The disease, hereditary motor and sensory neuropathy - Lom (HMSNL), presents with gait disturbances, difficulty in using the hands, muscle weakness and wasting and sensory loss. The concomitant impairment of the insulating myelin sheath surrounding nerve fibres (facilitating nerve conduction) and of the nerve fibres themselves suggests that the molecular defect lies in the basic mechanisms of interaction between the two main types of cell in the peripheral nervous system: the myelin-producing Schwann cell and the neuron. The two cells form the most complex system of communication in the human body, where signaling from one is vital for the development, functioning and survival of the other. Very little is known about the molecular mechanisms of this communication. At the same time, knowledge of the normal mechanisms of interaction is the key to better understanding of the mechanisms of disease in the peripheral nervous system and of the causes and possible prevention of the impairment of function. The newly identified HMSNL gene is probably involved in the signaling necessary for the development and functioning of the Schwann cell and for the survival of the nerve fibres. To gain an insight into the nature of the signaling cascade, we propose to use several complementary experimental approaches. We will create a mouse model of the human disease, to study its very early stages and subsequent evolution. In parallel, we will use molecular techniques and a yeast model, to identify other steps in the signaling cascade. The NHMRC-funded study will be part of a larger project conducted in collaboration with leading laboratories in the UK and the Netherlands, where other aspects of the molecular basis of the disease and of the role of the new gene will be examined.Read moreRead less
There are escalating numbers of Alzheimer�s disease sufferers. This Project aims to provide a better understanding of the fundamental process underlying the damage to brain circuitry in this condition. This proposal may provide key information regarding the relationship between the major pathological changes of Alzheimer�s disease, identifying the cellular mechanisms that are crucial to this process, and providing new avenues for therapeutic agents targeted at the earliest stage of AD.