Circadian clock disruption promotes the degeneration of dopaminergic neurons

Abstract Sleep and circadian rhythm disruptions are frequent comorbidities of Parkinson’s disease (PD), a disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although sleep/circadian disturbances can be observed years before diagnosing PD, it remains unclear whether circadian clocks have a causal role in the degenerative process. We demonstrated here that circadian clocks regulate the rhythmicity and magnitude of the vulnerability of DA neurons to oxidative stress in Drosophila . Circadian pacemaker neurons are presynaptic to a subset of DA neurons and rhythmically modulate their susceptibility to degeneration. The arrhythmic period ( per ) gene null mutation exacerbates the age-dependent loss of DA neurons and, in combination with brief oxidative stress, causes premature animal death. These findings suggest that circadian clock disruption promotes dopaminergic neurodegeneration.