Isoprenoids, Neuromelanin And Neuronal Vulnerability In Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$538,764.00
Summary
Parkinson's disease is a common and ultimately fatal brain disease which affects primarily normal movement. While a comparatively modest cell death occurs in other areas of the brain in Parkinson's disease, the motor symptoms result from the massive death of particular brain cells which are unique in that they contain a pigment called neuromelanin. This project aims to discover what makes the neuromelanin-containing cells of the brain particularly vulnerable to cell death in Parkinson's disease. ....Parkinson's disease is a common and ultimately fatal brain disease which affects primarily normal movement. While a comparatively modest cell death occurs in other areas of the brain in Parkinson's disease, the motor symptoms result from the massive death of particular brain cells which are unique in that they contain a pigment called neuromelanin. This project aims to discover what makes the neuromelanin-containing cells of the brain particularly vulnerable to cell death in Parkinson's disease. We recently found that neuromelanin pigment in the cells of people who have died with Parkinson's disease concentrate a fat-binding protein called alpha-synuclein which is thought to be important in causing cell death in Parkinson's disease. This association between the neuromelanin pigment and alpha-synuclein was not found in other cells in Parkinson brain which do not contain pigment, nor in the brains of healthy people. We also found that a third of neuromelanin is made up of a special group of fats called isoprenoids. Changes in these fats have already been reported in the blood in Parkinson's disease. We suggest that specific changes in the isoprenoid fats in neuromelanin in Parkinson's disease cause alpha-synuclein protein to accumulate on the fat in the pigment, as well as other cellular changes which are detrimental to the cell, ultimately leading to the death of the cell. These changes may explain for the first time why neuromelanin-containing brain cells are especially vulnerable in Parkinson's disease and provide new avenues for treating this disorder.Read moreRead less
Parkinson's Disease (PD) is one of the most common neurodegenerative disorders. Its incidence increases steadily with age affecting approximately 1% of the population at age 65 and up to 5% by the age of 85. At the time of diagnosis, patients suffer from a range of motor impairments that worsen over time. Pathologically these patients are characterised by the accumulation of a protein known as alpha-synuclein in specific types of nerve cells in their brain. However, the function of this protein ....Parkinson's Disease (PD) is one of the most common neurodegenerative disorders. Its incidence increases steadily with age affecting approximately 1% of the population at age 65 and up to 5% by the age of 85. At the time of diagnosis, patients suffer from a range of motor impairments that worsen over time. Pathologically these patients are characterised by the accumulation of a protein known as alpha-synuclein in specific types of nerve cells in their brain. However, the function of this protein is unknown. This proposal will clarify the role of alpha-synuclein in PD and normal CNS function and provide new potential therapeutic targets for the treatment of PD and other neurodegenerative disorders in which oxidative stress, excitotoxicity and central nervous system trauma have been implicated.Read moreRead less
Cellular Effects Of Glucocerebrosidase (GBA) Mutations In Lewy Body Diseases
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Approximately 1 in 100 people are carriers of mutations in the glucocerebrosidase (GBA) gene and are at considerably greater risk of diseases characterised clinically by parkinsonism and by the presence of Lewy body-related pathology. This study will provide tissue-based evidence of the cellular lipid and protein changes relating to Lewy body formation in patients with GBA mutations, providing the information necessary to identify the pathways and mechanisms involved.
Differential Regulation Of Human Tyrosine Hydroxylase Isoforms And The Development Of Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$325,591.00
Summary
Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than othe ....Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than other dopaminergic cells in the brain. Tyrosine hydroxylase controls the rate of dopamine synthesis. Humans are unique in that they contain four isoforms of tyrosine hydroxylase and therefore they have the potential to alter the regulation of dopamine synthesis in ways that other species do not. Recent developments in our laboratories have suggested that particular isoforms of tyrosine hydroxylase may have either a role in the susceptibility of dopaminergic neurons to degeneration in Parkinson's disease or a role in the timing of the symptoms of the disease. We have demonstrated differences in the distribution of the human TH isoforms within the substantia nigra, with certain isoforms being more prevalent in the susceptible ventral cells. We have also shown that there are major differences in the regulation of the four human tyrosine hydroxylase isoforms. Some isoforms will be more sensitive to conditions that occur with high frequency stimulation of neurons and some to low frequency sustained stimulation. This would provide a mechanism by which differential distribution of the human TH isoforms would result in altered dopamine synthesis in different parts of the human brain and this may in turn lead to either increased susceptibility to, or earlier appearance of symptoms of, Parkinson's disease.Read moreRead less
Secretion Of Alpha-synuclein: A Diagnostic Marker For Parkinsons Disease And A Clue To Its (patho)physiology
Funder
National Health and Medical Research Council
Funding Amount
$634,051.00
Summary
We have found that a protein, alpha-synuclein is low in people with Parkinson's Disease. We wish to see if this can be used as a diagnostic test for the condition. Alpha-Synuclein is thought to be important in causing Parkinson's Disease. We suspect that by finding out why less of this protein enters the blood stream in Parkinson's Disease, we may discover clues as to how alpha-synuclein causes problems in this condition.
By the time a patient first presents with symptoms of Parkinson's disease at the clinic, a large proportion (60-70%) of the cells in a specific part of the brain have been destroyed. This degeneration progresses until, within a few years, most of the cells have died. This project investigates the mechanisms involved in the continued death of cells and a possible new therapy that interrupts the progression. If the aims of this proposal are met, the drug could rapidly go to clinical trial.
Block Of ER-Golgi Vesicular Transport By Alpha-Synuclein As An Underlying Cause Of Parkinson's Disease.
Funder
National Health and Medical Research Council
Funding Amount
$361,091.00
Summary
Parkinson's disease, a progressive disorder of the central nervous system, is the most common neurodegenerative disorder after Alzheimer's disease. Parkinson's Disease is the direct result of the loss of dopamine producing cells in a portion of the brain called the substantia nigra. The loss of dopamine, a chemical messenger responsible for transmitting signals within the brain causes critical nerve cells in the brain to fire out of control, leaving patients unable to direct or control their mov ....Parkinson's disease, a progressive disorder of the central nervous system, is the most common neurodegenerative disorder after Alzheimer's disease. Parkinson's Disease is the direct result of the loss of dopamine producing cells in a portion of the brain called the substantia nigra. The loss of dopamine, a chemical messenger responsible for transmitting signals within the brain causes critical nerve cells in the brain to fire out of control, leaving patients unable to direct or control their movement in a normal manner. A protein, alpha synuclein has been shown to be a central component in Parkinson's disease. Our recent data, in collaboration with international colleagues, has led us to propose a new model for the mechanism by which alpha synuclein may cause Parkinson's disease that involves alpha synuclein interfering with how other proteins are transported within the cell. This proposal comprises a series of biomolecular experiments designed to test this model and provide new insights into therapies for Parkinson's patients.Read moreRead less
Alpha-synuclein Metabolism In Human Neurodegenerative Disease
Funder
National Health and Medical Research Council
Funding Amount
$381,430.00
Summary
Alpha-synuclein is an abundant brain protein of unknown function. Gene mutations have been linked to rare cases with inherited Parkinson s disease. Now this protein is believed to play an important role in all forms of Parkinson s disease, Lewy body dementia, and multiple system atrophy. These diseases are designated as synucleinopathies to emphasize the potential importance of alpha-synuclein in these disease. Recent studies suggest alpha-synuclein may also contribute to many other human diseas ....Alpha-synuclein is an abundant brain protein of unknown function. Gene mutations have been linked to rare cases with inherited Parkinson s disease. Now this protein is believed to play an important role in all forms of Parkinson s disease, Lewy body dementia, and multiple system atrophy. These diseases are designated as synucleinopathies to emphasize the potential importance of alpha-synuclein in these disease. Recent studies suggest alpha-synuclein may also contribute to many other human diseases, including Alzheimer s disease. The reason how and why alpha-synuclein is involved in so many human neurological diseases is not clear. We recently discovered that alpha-synuclein in normal human brain exists in multiple form of N-terminal fragments, presumably generated through certain endogenous enzymes. These cleaved products are markedly increased in Parkinson s disease. Studies by other groups suggest alpha-synuclein and fragments may be released to the cerebrospinal fluids. Based on these findings, we hypothesize that alpha-synuclein is modified by specific enzymes in neurons and released. This is probably a normal alpha-synuclein metabolic pathway whose homeostasis may be, for reasons yet to be understood, altered in synucleinopathies. Similar mechanism may be also involved in other common diseases in which the protein is believed to play a role. This project aims to elucidate the potential role of alpha-synuclein metabolism in Parkinson s and related diseases by examining alpha-synuclein metabolites in the brains affected by these diseases. Results from this grant will provide new information about alpha-synuclein metabolism in neurons, new insights into the mechanistic involvement of alpha-synuclein in these neurodegenerative diseases. Antibody reagents generated from this study may be valuable in neuropathological and clinical assessment of changes in synucleinopathies.Read moreRead less