Parkinson's disease-associated <i>PINK1</i> loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss.

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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.

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