Systems Regulating and Inducing Dopaminergic Cell Death in Parkinson’s Disease: an Analysis of Signalling Associated with Parkinson's Disease Models

Abstract

Parkinson’s disease (PD) is characterized by the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Mechanisms regulating this neurodegeneration, however, are unclear. Evidence from PD pathology and models of PD, indicate mitochondrial disfunction triggers several death signalling pathways. Accordingly, in vivo and in vitro mitochondrial stress models of PD were employed to explore the role of two divergent molecular influences on dopaminergic neuronal survival. We examined neuroinflammatory and death signalling pathways arising from MPTP-induced mitochondrial stress. Interferon-gamma (IFN-ɣ) is a cytokine known to activate cellular components of inflammation, including microglia of the central nervous system (CNS). Results of a screen for cytokines in PD patient plasma revealed elevated levels of IFN-ɣ, suggesting a correlation between IFN-ɣ and PD associated DA cell death. In an MPTP mouse model of PD, germline deletion of IFN-ɣ improved survival of DA neurons and the nigrostriatal system, along with a reduction in microglia activation. Employing a survival co-culture system of neurons and microglia, it was found that neutralizing IFN-ɣ reduced DA cell loss induced by the mitochondrial complex I inhibitor, rotenone. DA cell death required localized microglia, activated through the IFN-ɣ-receptor (IFN-ɣ-R), with DA survival inversely proportional to IFN-ɣ expression, found to be up-regulated following rotenone. Investigation of the calpain-Cdk5-MEF2 signalling pathway in the MPTP model of DA cell death, motivated an examination of the nuclear orphan receptor, Nur77, following a review of potential MEF2 regulatory targets. MPTP induced a reduction in Nur77 mRNA from basal ii levels in SNc tissue, further regulated by ectopic Nur77 expression. These results strengthened our new model of MEF2 Nur77 regulation in DA neurons. In MPP+/MPTP DA survival experiments, loss in germline Nur77 expression presented an elevation in DA neuronal death both in vitro and in vivo, with a greater impairment in the nigrostriatal circuitry in comparison with normal expressing animals and cells. Dopaminergic supersensitivity related to Nur77 deficiency was attenuated with the ectopic expression of AV-Nur77 in vivo. These opposing mediators of survival yield new mechanisms by which DA neurons die, suggesting a mutitargeting approach to halt the progression of DA cell death.