A Single Dopamine Pathway Underlies Progressive Locomotor Deficits in a Drosophila Model of Parkinson Disease

Abstract

Expression of the human Parkinson-disease-associated protein α-synuclein in all Drosophila neurons induces progressive locomotor deficits. Here, we identify a group of 15 dopaminergic neurons per hemisphere in the anterior medial region of the brain whose disruption correlates with climbing impairments in this model. These neurons selectively innervate the horizontal β and β' lobes of the mushroom bodies, and their connections to the Kenyon cells are markedly reduced when they express α-synuclein. Using selective mushroom body drivers, we show that blocking or overstimulating neuronal activity in the β' lobe, but not the β or γ lobes, significantly inhibits negative geotaxis behavior. This suggests that modulation of the mushroom body β' lobes by this dopaminergic pathway is specifically required for an efficient control of startle-induced locomotion in flies.

Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function

“…[63–68]), but actual cell loss was sometimes contested [69, 70]. Here we report that reducing TH levels in specific neurons was sufficient to accelerate ARLI, as was also shown in our previous study [27]. In the latter, accelerated ARLI was attributed not to cell loss, but to age-related alterations in contacts onto the mushroom bodies from a subset of ~15 PAM neurons, when they express α-synuclein (a protein involved in PD).…”

“…However, TH-D'-Gal4 targets other dopaminergic neurons, outside the PPL1, in the PPL2 and PPM3 clusters, which may contribute to the observed effect on ARLI. Therefore we used an alternative strategy [27]: inactivating Drosophila TH by targeted RNAi. By driving TH RNAi expression with MZ840-Gal4 , which is expressed in only one PPL1 neuron (MB-V1) and in other non-dopaminergic brain cells [44], the two MB-V1 neurons should be the only affected ones.…”

“…They are thus often used to assay functional aging, particularly in insects (reviewed in [19]). Dopaminergic (DA) circuits are important for proper motor control and abilities, both in mammals [20–22] and Drosophila [23–27]. This importance is illustrated by the devastating effect of specific DA neuronal loss on motor control in Parkinson's disease (PD), for which age is the major risk factor [28].…”

Analysis of survival, gene expression and behavior following chill-coma in the medfly Ceratitis capitata: Effects of population heterogeneity and age

“…Our first specific objective was to characterize subgroups in medfly populations with different cold tolerance, analyzing their survival parameters and negative geotaxis performance. This behavioral assay reflects the locomotor ability of flies to respond to a mechanical stimulus (Gargano et al, 2005;Riemensperger et al, 2013), and was useful to corroborate differences between flies with reversible and irreversible damage after chill-coma, since the neuromuscular activity is affected by cold exposure. The second objective was to find a possible association between these parameters and the cold stress response at a gene expression level.…”

Distinct dopamine neurons mediate reward signals for short- and long-term memories

“…Similar to midbrain dopamine neurons in mammals (26,27), the structure and function of PAM cluster neurons are heterogeneous, and distinct dopamine neurons intersect unique segments of the MB lobes (19,(28)(29)(30)(31)(32)(33)(34). Further circuit dissection is thus crucial to identify candidate synapses that undergo associative modulation.…”