Parkinson's disease (PD) is the most prevalent movement disorder in the United States. Despite recent advances in treatment there remain pressing needs for novel therapies that halt disease progression, means for early diagnosis and methods to identify environmental and genetic risk factors. PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) accompanied by gliosis and evidence of oxidative stress, mitochondrial dysfunction and excessive iron deposition. Although dopamine metabolism, environmental and genetic factors have been implicated in the etiology of idiopathic PD, the precise cause is unknown. In this application, the investigators will exploit the observation that MPTP toxicity is genetically determined in mice to characterize a novel molecular signaling pathway that links this xenobiotic to neuronal death and several of the pathological hallmarks of PD. MPTP is a xenobiotic neurotoxin that produces many of the features of PD in animal models and man. Furthermore, susceptibility to MPTP is species- dependent and is inherited as a dominant trait in mice. Therefore, the murine MPTP model represents a unique opportunity to dissect the interaction between a prototypic exogenous neurotoxin and genetic risk factors that may contribute to the pathogenesis of PD. Using a novel chimeric primary culture paradigm where isolated astrocytes or neurons from resistant or sensitive strains of mice are co-cultured in different combinations, the genetic susceptibility to MPTP is conferred by astrocytes. This led the investigators to uncover elements of a previously undescribed response pathway to MPTP in vivo that includes alterations in gene expression in astrocytes. As this response involves dopamine metabolism, oxidative stress and the local production of endogenous neurotoxins, such as iron, they hypothesize that it is capable both of linking MPTP to the selective loss of SNpc dopaminergic neurons and accounting for some of the ancillary pathological findings in PD. Furthermore, as dopamine but not other catecholamines triggers this pathway it can account for the neuronal specificity of MPTP killing.
