Role of the circadian protein Nocturnin in modulating oxidative stress in substantia nigra dopaminergic neurons

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Abstract Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by severe movement disorders that result from selective loss of dopamine neurons from the substantia nigra in the midbrain. In addition to the movement disorders, the most common non-motor manifestation of PD is a major disruption in sleep-wake cycles, with ~80% of patients exhibiting excessive daytime sleepiness or changes in sleep timing and reduced circadian amplitudes. The cause of the selective dopaminergic cell death is not known but appears to be through various cellular insults that result in toxic aggregation of the a- synuclein protein and increased oxidative stress. Although the existing data make difficult to determine whether oxidative stress or protein aggregation is the initiating event, these two processes clearly impact each other, and a growing body of evidence implicates oxidative stress as being involved in at least the propagation of cellular injury that leads to neuropathology in PD. In this exploratory application, we will explore the role of the circadian protein Nocturnin in the pathogenesis of PD. Our data suggest that Nocturnin is an important modulator of oxidative stress, with higher levels exacerbating stress and lower levels providing protective effects. Nocturnin has been reported to be upregulated in the substantia nigra in PD patients suggesting that it may be playing a role in excessive oxidative stress responses that contribute to pathogenesis and we will examine this link through mechanistic work in both cells and mice in this proposal. There are currently no treatments that prevent neuronal cell loss in PD and we hypothesize that reduction of oxidative stress through the inhibition of Nocturnin might break the cycle of cell death.