An Early Disturbance in Serotonergic Neurotransmission Contributes to the Onset of Parkinsonian Phenotypes in Drosophila melanogaster

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor symptoms and dopaminergic cell loss. A pre-symptomatic phase characterized by non-motor symptoms precedes the onset of motor alterations. Two recent PET studies in human carriers of mutations associated with familial PD demonstrate an early serotonergic commitment—alteration in SERT binding—before any dopaminergic or motor dysfunction, that is, at putative PD pre-symptomatic stages. These findings support the hypothesis that early alterations in the serotonergic system could contribute to the progression of PD, an idea difficult to be tested in humans. Here, we study some components of the serotonergic system during the pre-symptomatic phase in a well-characterized Drosophila PD model, Pink1B9 mutant flies. We detected lower brain serotonin content in Pink1B9 flies, accompanied by reduced activity of SERT before the onset of motor dysfunctions. We also explored the consequences of a brief early manipulation of the serotonergic system in the development of motor symptoms later in aged animals. Feeding young Pink1B9 flies with fluoxetine, a SERT blocker, prevents the loss of dopaminergic neurons and ameliorates motor impairment observed in aged mutant flies. Surprisingly, the same pharmacological manipulation in young control flies results in aged animals exhibiting a PD-like phenotype. Our findings support that an early dysfunction in the serotonergic system precedes and contributes to the onset of the Parkinsonian phenotype in Drosophila.

Parkinsonian phenotypes induced by Synphilin-1 expression are differentially contributed by serotonergic and dopaminergic circuits and suppressed by nicotine treatment

“…However, the extent to which the dopaminergic and serotonergic neural systems interact functionally in the Drosophila brain has not been thoroughly examined. A recent study suggests that this is the case, demonstrating that alteration of the serotonergic system in young animals affects the survival of dopaminergic neurons [ 28 ]. Our study advances this issue by showing that serotonergic and dopaminergic systems influence the detection of PD-associated symptoms in flies.…”

Modeling neurodegenerative and neurodevelopmental disorders in theDrosophilamushroom body

“…The increased energetic demand suggests that PINK1 mutations affect mitochondrial function ( Pilsl and Winklhofer 2012 ). Neurons are lost in the PPL1, PPL2, PPM 1/2, and PPM3 clusters ( Pirooznia et al 2020 ; Zárate et al 2022 ). In Drosophila , PINK1 binds directly to the mitochondrial protein PGAM5 to activate mitochondrial degradation followed by cell loss ( Imai et al 2010 ).…”

“…In Drosophila , l -DOPA decreases the innervation of the α/α′ lobes by serotonergic dorsal paired medial (DPM) neurons ( Niens et al 2017 ). Furthermore, the loss of PPL2 neurons that innervate the MB dendrites (among other brain regions) can be rescued by increasing serotonergic activity ( Zárate et al 2022 ). Overall, research in Drosophila has shed light on the molecular mechanisms that potentially drive the pathophysiology of PD ( Shukla et al 2014 ; Maitra et al 2019 ; Ma et al 2022 ; Zhang et al 2023 ).…”