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

Parkinson's disease (PD) is frequently linked to the demise of dopamine-producing neurons in the substantia nigra, yet various other cell types also suffer damage prior to neuronal loss. Recent research has connected oligodendrocytes to the early phases of PD, although the extent of their involvement remains unclear. PINK1 is defective in inherited PD, and through comprehensive single-cell sequencing of a Drosophila Pink1 model, researchers observed substantial gene deregulation in ensheathing glia (EG), cells with functional similarities to oligodendrocytes.

The absence of PINK1 results in EG abnormalities, akin to the reactive response of EG following nerve injury. By examining cell-type-specific transcriptomics, the study identified deregulated genes in EG as potential functional modifiers. Specifically, downregulating two trafficking factors in EG, Vps35 and Vps13, which are also mutated in PD, was enough to restore neuronal function and safeguard against dopaminergic synapse loss.

The findings reveal that PINK1 loss in neurons initiates an injury-like response in EG, and conversely, PINK1 loss in EG disrupts neuronal function. Vesicle trafficking components, which may govern membrane interactions between organelles in EG, appear to play a role in preserving neuronal health and ultimately preventing dopaminergic synapse loss.

This study underscores the crucial role of glial support cells in PD pathogenesis and pinpoints vesicle trafficking within these cells in disease progression.