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Asymmetric Presynaptic Depletion of Dopamine Neurons in a Drosophila Model of Parkinson's Disease.

ABSTRACT: Parkinson's disease (PD) often displays a strong unilateral predominance in arising symptoms. PD is correlated with dopamine neuron (DAN) degeneration in the substantia nigra pars compacta (SNPC), and in many patients, DANs appear to be affected more severely on one hemisphere than the other. The reason for this asymmetric onset is far from being understood. Drosophila melanogaster has proven its merit to model molecular and cellular aspects of the development of PD. However, the cellular hallmark of the asymmetric degeneration of DANs in PD has not yet been described in Drosophila. We ectopically express human α-synuclein (hα-syn) together with presynaptically targeted syt::HA in single DANs that innervate the Antler (ATL), a symmetric neuropil located in the dorsomedial protocerebrum. We find that expression of hα-syn in DANs innervating the ATL yields asymmetric depletion of synaptic connectivity. Our study represents the first example of unilateral predominance in an invertebrate model of PD and will pave the way to the investigation of unilateral predominance in the development of neurodegenerative diseases in the genetically versatile invertebrate model Drosophila.

SUBMITTER: Zhang J

PROVIDER: S-EPMC10218197 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Asymmetric Presynaptic Depletion of Dopamine Neurons in a <i>Drosophila</i> Model of Parkinson's Disease.

Zhang Jiajun J Lentz Lucie L Goldammer Jens J Iliescu Jessica J Tanimura Jun J Riemensperger Thomas Dieter TD

International journal of molecular sciences 20230511 10

Parkinson's disease (PD) often displays a strong unilateral predominance in arising symptoms. PD is correlated with dopamine neuron (DAN) degeneration in the substantia nigra pars compacta (SNPC), and in many patients, DANs appear to be affected more severely on one hemisphere than the other. The reason for this asymmetric onset is far from being understood. <i>Drosophila melanogaster</i> has proven its merit to model molecular and cellular aspects of the development of PD. However, the cellular ...[more]

PMID: 37239942

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Project description:BackgroundAsymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression.ObjectivesThe objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4-year progression in drug-naïve PD.MethodsFrom the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right-handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single-photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD-left), and on the right side in 106 patients (PD-right); we compared them with 196 healthy controls. Patients were followed longitudinally (2-year and 4-year visits), examining their clinical, cognitive, and imaging data.ResultsAt baseline, the PD-left group showed worse performance on the Symbol Digit Modality Test, an attention and processing-speed test, and lower cerebrospinal fluid β-amyloid levels than the PD-right group. These differences were maintained at follow-up, declining over time in both groups. By contrast, the PD-right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD-right group showed a steeper decline, particularly during the first 2-year follow-up. Putaminal asymmetry assessed at baseline was maintained over time.ConclusionsThese findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dataset Information

Asymmetric Presynaptic Depletion of Dopamine Neurons in a Drosophila Model of Parkinson's Disease.

Publications

Asymmetric Presynaptic Depletion of Dopamine Neurons in a <i>Drosophila</i> Model of Parkinson's Disease.

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Dataset Information

Asymmetric Presynaptic Depletion of Dopamine Neurons in a Drosophila Model of Parkinson's Disease.

Publications

Asymmetric Presynaptic Depletion of Dopamine Neurons in a &lt;i&gt;Drosophila&lt;/i&gt; Model of Parkinson's Disease.

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OmicsDI is part of the ELIXIR infrastructure

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Asymmetric Presynaptic Depletion of Dopamine Neurons in a <i>Drosophila</i> Model of Parkinson's Disease.