From retina to brain: retinal dysfunction and dopaminergic neurodegeneration in Drosophila models of Parkinson’s disease

Abstract

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta. Although PD is primarily defined as a motor disorder, prodromal non-motor symptoms - such as circadian clock desynchronization and sleep disturbances - can emerge years before clinical diagnosis. Increasing evidence suggests that these non-motor manifestations, particularly circadian disruption, may contribute to disease progression. However, it remains unclear whether circadian dysfunction actively drives neurodegeneration or arises as a consequence of ongoing neuronal loss. In this study, we employed genetic models of PD in Drosophila melanogaster to investigate these relationships. Specifically, we examined the effects of parkin (park) silencing and neuronal expression of human α-Synuclein on photoreceptor morphology and function. Furthermore, we assessed whether mitophagy impairment or synucleinopathy confined to the visual system can influence the onset and progression of PD-related phenotypes. Given that sleep fragmentation is a common feature in PD patients, we also analyzed sleep patterns in flies, focusing on sleep duration. In parallel, we evaluated dopaminergic neuron degeneration, with particular emphasis on the protocerebral anterior medial (PAM) cluster, which plays a critical role in the regulation of sleep and locomotor activity. Taken together, our findings highlight the importance of elucidating the interplay between retinal cells disruption and neurodegeneration in deeper parts of the brain in Parkinson’s disease.