A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration

Abstract

Summary: Pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) induce an age-dependent loss of dopaminergic (DA) neurons. We have identified Furin 1, a pro-protein convertase, as a translational target of LRRK2 in DA neurons. Transgenic knockdown of Furin1 or its substrate the bone morphogenic protein (BMP) ligand glass bottom boat (Gbb) protects against LRRK2-induced loss of DA neurons. LRRK2 enhances the accumulation of phosphorylated Mad (pMad) in the nuclei of glial cells in the vicinity of DA neurons but not in DA neurons. Consistently, exposure to paraquat enhances Furin 1 levels in DA neurons and induces BMP signaling in glia. In support of a neuron-glial signaling model, knocking down BMP pathway members only in glia, but not in neurons, can protect against paraquat toxicity. We propose that a neuron-glial BMP-signaling cascade is critical for mediating age-dependent neurodegeneration in two models of Parkinson’s disease, thus opening avenues for future therapeutic interventions. : Mutations in the Parkinson’s-related gene LRRK2 lead to an age-dependent loss of dopaminergic neurons. Maksoud et al. show that this loss is mediated by Furin 1, a translational target of LRRK2. A critical step mediating this neurotoxic effect is a neuron-glia BMP-signaling cascade that is induced by Furin 1. Keywords: Parkinson’s disease, LRRK2, translation, neurodegeneration, glia, Furin1, BMP signaling, aging