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Parkinson’s Disease-Associated Pink1 Loss Disrupts Ensheathing Glia And Causes Dopaminergic Neuron Synapse Loss

ABSTRACT: Parkinson’s disease (PD) is commonly associated with the loss of dopaminergic neurons in the substantia nigra, but many other cell types are affected even before neuron loss occurs. Recent studies have linked oligodendrocytes to early stages of PD, though their precise role is still unclear. PINK1 is mutated in familial PD, and through unbiased single-cell sequencing of the entire brain of Drosophila Pink1 models, we observed significant gene deregulation in ensheathing glia (EG); cells that share functional similarities with oligodendrocytes. We found that the loss of Pink1 leads to abnormalities in EG, similar to the reactive response of EG seen upon nerve injury. Using cell-type-specific transcriptomics, we identified deregulated genes in EG as potential functional modifiers. Specifically downregulating two trafficking factors in EG, Vps35 and Vps13, also mutated in PD, was sufficient to rescue neuronal function and protect against dopaminergic synapse loss. Our findings demonstrate that Pink1 loss in neurons triggers an injury-like response in EG, and that Pink1 loss in EG in turn disrupts neuronal function. Vesicle trafficking components, which may regulate membrane interactions between organelles in EG, seem to play a role in maintaining neuronal health and ultimately preventing dopaminergic synapse loss. Our work highlights the essential role of glial support cells in the pathogenesis of PD and identifies vesicle trafficking within these cells in disease progression.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE322929 | GEO | 2026/03/05

REPOSITORIES: GEO

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Project description:Loss-of-function mutations in the parkin gene can cause early onset Parkinson’s disease, a movement disorder resulting from the selective degeneration of dopaminergic neurons in the basal ganglia. Analogously, movement deficits and loss of a subset of dopaminergic neurons are observed in Drosophila melanogaster homozygous for null mutations in parkin. Parkin is an E3 ubiquitin ligase that functions with the mitochondrial localized serine/threonine kinase PINK1 in a pathway required to maintain mitochondrial integrity. We previously established that the PINK1/Parkin pathway functions in Drosophila dopaminergic and cholinergic neurons to maintain mitochondrial membrane potential. However, the mechanisms through which the PINK/Parkin pathway selectively impacts dopaminergic neuron survival remains unclear, as do the mechanisms that lead to the selective vulnerability of dopaminergic neurons in Parkinson’s disease. Because the transcriptome of a cell determines its identity we hypothesized that knowledge of the transcriptional alterations that occur in dopaminergic neurons isolated from parkin null Drosophila would provide insight into the mystery of selective vulnerability in Parkinson's disease. Results: To test our hypothesis we measured the transcriptome of dopaminergic and cholinergic neurons isolated from isogenic heterozygous and homozygous parkin null mutants using a novel flow cytometry-based method we developed. Computational analysis and experimental confirmation demonstrate that our method allows for the successful expression analysis of defined neural subsets from the Drosophila brain. In addition, our dataset implicates iron handling and dopamine signaling as being significantly dysregulated in parkin null dopaminergic neurons. Conclusions: Our flow cytometry-based method allows for the isolation and microarray analysis of neuronal subsets from the adult Drosophila brain. Our microarray analyses implicate iron handling and dopamine metabolism as contributing factors in the etiology of parkin-associated early onset Parkinson’s disease. Here we provide a novel dataset that may serve as a foundation for subsequent functional analyses of the pathways underlying neuronal selective vulnerability in Parkinson's disease.

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Parkinson’s Disease-Associated Pink1 Loss Disrupts Ensheathing Glia And Causes Dopaminergic Neuron Synapse Loss

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