Pre-Fibrillar [alpha]-Synuclein Mutants Cause Parkinson's Disease-Like Non-Motor Symptoms in Drosophila

Parkinson's disease (PD) is linked to the formation of insoluble fibrillar aggregates of the presynaptic protein [alpha]-Synuclein ([alpha]S) in neurons. The appearance of such aggregates coincides with severe motor deficits in human patients. These deficits are often preceded by non-motor symptoms such as sleep-related problems in the patients. PD-like motor deficits can be recapitulated in model organisms such as Drosophila melanogaster when [alpha]S is pan-neurally expressed. Interestingly, both these deficits are more severe when [alpha]S mutants with reduced aggregation properties are expressed in flies. This indicates that that [alpha]S aggregation is not the primary cause of the PD-like motor symptoms. Here we describe a model for PD in Drosophila which utilizes the targeted expression of [alpha]S mutants in a subset of dopadecarboxylase expressing serotonergic and dopaminergic (DA) neurons. Our results show that targeted expression of pre-fibrillar [alpha]S mutants not only recapitulates PD-like motor symptoms but also the preceding non-motor symptoms such as an abnormal sleep-like behavior, altered locomotor activity and abnormal circadian periodicity. Further, the results suggest that the observed non-motor symptoms in flies are caused by an early impairment of neuronal functions rather than by the loss of neurons due to cell death.