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New Dopaminergic Neurons In The Parkinson's Disease Striatum: Establishment Of Phenotype, Function And Origin.
Funder
National Health and Medical Research Council
Funding Amount
$156,493.00
Summary
Parkinson s disease is usually associated with loss of dopamine cells that send nerves from the substantia nigra to the striatum. However, we have found large numbers of apparently new dopaminergic cells in post mortem tissue from the striatum of 10 patients with Parkinson s disease but not in 5 age-matched controls. Our aims are firstly to determine whether these cells are indeed dopaminergic neurons by establishing their neurochemical and morphological profiles. This is required to determine w ....Parkinson s disease is usually associated with loss of dopamine cells that send nerves from the substantia nigra to the striatum. However, we have found large numbers of apparently new dopaminergic cells in post mortem tissue from the striatum of 10 patients with Parkinson s disease but not in 5 age-matched controls. Our aims are firstly to determine whether these cells are indeed dopaminergic neurons by establishing their neurochemical and morphological profiles. This is required to determine whether these apparently dopaminergic cells do indeed produce the neurotransmitter dopamine and to determine to what class of neuron they belong. The latter is important to establish whether they act locally in the striatum or extend their influence over a larger area of the brain. Secondly we shall assess their function in human and rat tissue. We shall determine whether their number is related to the severity of damage in Parkinson s disease, or whether L-DOPA therapy, which most patients receive, plays any role in their appearance. These experiments will lay the ground work to allow us to determine whether these cells are beneficial or harmful. Lastly, we shall determine where these cells come from. We shall determine whether they have always been present but have taken on a new function, or whether they are in fact new cells which have been born recently. This knowledge is essential if we are to be able to change their numbers to improve treatment of Parkinson s disease. We estimate that there are up to 66,000 of these dopaminergic cells in each striatum of patients with Parkinson s disease. This is enough to have a significant impact on the manifestation of the disease. These cells might be beneficial, allowing the brain to maintain essential functions for longer or they might be harmful playing a role in either development of Parkinson s disease itself or the harmful side effects of L-DOPA therapy.Read moreRead less
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