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Time course of nigro-striatal neurodegeneration : a novel toxin-induced model showing neuropathological features of parkinsonism Schulz, Jeff

Abstract

Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) is a neurodegenerative disease characterized by features of amyotrophic lateral sclerosis, parkinsonism, and a dementia reminiscent of Alzheimer's disease. Occurring primarily on the island of Guam, it has been linked epidemiologically to the consumption of seeds from the cycad palm Cycas micronesica. To further investigate the 'cycad hypothesis' of ALS-PDC, a cycad model has been developed in which mice are fed cycad as prepared by the indigenous people of Guam. Initial studies have shown that cycad-fed mice develop motor, cognitive and neuropathological changes similar to those of ALS-PDC. This study was designed to assess changes related to parkinsonism by investigating motor dysfunction and neuropathological changes related to dopamine in the basal ganglia. Cycad-fed animals demonstrated dysfunction in several motor tests, including the de Medinaceli gait length task. However, it was not possible to confirm that the motor phenotype was a result of dysfunction of the basal ganglia because of the potentially confounding effect of motor neuron involvement. Neuropathological analysis revealed a slow, progressive change in striatal dopaminergic integrity as evidenced by decreases in striatal tyrosine hydroxylase and dopamine transporter immunoreactivity as well as a compensatory increase in dopamine D2 receptor levels. Analysis of apopototic cell death showed the presence of activated caspase-3 dopaminergic cells in the substantia nigra pars compacta which was accompanied by astrogliosis. Notably, these neuropathological changes persisted despite the cessation of cycad feeding. In a subsequent experiment, measurement of striatal dopamine levels failed to detect a difference in cycad-fed animals, although this may be due to the fact that the tissue might have been collected before any significant neuropathological changes had occurred. Taken together, the results of this study provide further support for the 'cycad hypothesis' of ALS-PDC and show that features of parkinsonism are present in the cycad model.

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