Glia and CED-1/MEGF10 independently drive dopamine neurodegeneration in Parkinson's disease models.

Abstract

Parkinson's disease (PD) is marked by progressive dopamine neuron degeneration, but the phagocytic receptors and cells that clear neuronal corpses remain ill-defined. Moreover, while other cell types like glia, epithelia, and muscle are also impacted in PD, their roles in disease progression are unclear. We report that multiple nonneuronal cell types modulate dopamine neurodegeneration in Caenorhabditis elegans. Astrocyte-like CEPsh glia respond to neuronal stress and regulate dopamine biosynthesis enzyme CAT-2/TH and transporter DAT-1/SLC6A3. They are neurotoxic by downregulating neuroprotective dopamine levels. Degenerating dopamine neurons expose phosphatidylserine (PS) via the necrotic phospholipid scramblase ANOH-1/TMEM16F and ABC transporter CED-7/ABCA1. Epithelia and muscle cells then phagocytose dopamine neuron corpses and drive neuron death and clearance via the conserved PS receptor CED-1/Draper/MEGF10. Depleting ced-1 protects against loss of dopamine neurons and associated animal behaviors in a PD model. Evolutionary conservation of the underlying components and their effects across PD models suggests that multi-organ engagement may be a shared feature of dopamine neurodegeneration in PD.

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