Programming Adult Neurological Disease Parkinsons Disease

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A long-term effect of fetal neuromotor programming may be an increased predisposition to adult or later onset neurological disorders, for example, Parkinsons disease. Parkinson's disease is a progressive motor pathology characterised by the loss of capacity to initiate and control appropriate voluntary movements. Patients do not become symptomatic until they have lost more than 60-80% of their dopamine-producing neurons in the substantia nigra pars compacta of the basal ganglia, a process that can take over a decade. Nigral dopamine cell numbers decline during normal ageing, but not everyone develops the disease before they die, presumably because the cell loss "threshold" has not been reached; in Parkinson's disease, this rate of cell loss is accelerated significantly by an unknown mechanism. It is possible that individuals born with fewer dopamine-producing nigral cells are more likely to become symptomatic than someone of the same age and sex who starts life with a normal or optimal nigral cell number.

There is emerging evidence that alterations to prenatal dopaminergic neurogenesis might be linked to the onset of Parkinsons disease, at least in some cases.1 This has come largely from the identification and role of the transcription factors, including Nurrl, that regulate dopaminergic neurogenesis during development of the brain. Alterations in the timing of onset and/or the level of expression of these transcription factors during fetal life may predispose mature dopaminergic nigral neurons to earlier and possibly accelerated cell death in at least some cases of idiopathic Parkinson's disease.106 The current understanding of the cellular regulation of trophic factors important in the development and maintenance of healthy synapses is relatively sparse. However, immature neurons are thought to be apoptosed by trophic factor deprivation if they do not form functional synapses with their targets. While this is a normal and important part of proper development of the nervous system, it may also adversely reduce cell numbers when interference alters synaptic development. Therefore, the number of dopaminergic nigral neurons produced that survive to maturity, and the lifespan of those that do mature, may be compromised by an adverse in utero environment during dopaminergic neurogenesis that alters the time of onset, effectiveness or availability of trophic factors and/or transcription factors.106 For example, it is known that an excess of retinoic acid (part of the Vitamin A molecule) inhibits the transcriptional activity of Nurrl and is teratogenic. Nurrl is thought to play a key role in differentiation, maturation and maintenance of brain dopaminergic neurons and neural circuits.107 There is also evidence that it has an instructive role in dopamine synthesis and storage in the adult brain.108 In rats exposed prenatally to excess retinoic acid between gestational days 14-16, cerebellar weight was reduced and the cluster of behavioural and motor effects was consistent with disturbance in the mesolimbic dopamine system.109 Disturbances of the development of the dopaminergic neural system have also been associated with attention deficit disorder and schizophrenia, although direct evidence for the latter has yet to be presented.110

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