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.

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson’s Disease

“…POM possesses selective and potent TNF-α inhibitory activity, therefore suggesting that the inhibition of inflammatory pathways triggered by the ortholog of this cytokine Eiger in LRRK2 WD40 flies may be the main neuroprotective mechanism of this agent. Of note, a recent study has provided a clear link between dysfunctional LRRK2 in dopamine neurons and altered glial response in Drosophila PD models, by showing that the genetic inhibition of the pro-inflammatory bone morphogenic protein (BMP) signaling in glia, was protective against PD-related neurotoxicity in aged mutant flies (Maksoud et al, 2019). Moreover, although further studies are needed to fully elucidate the functional targets of POM in PD, we suggest that modulation of phagocytosis may represent an additional mechanism of neuroprotection downstream to the anti-inflammatory activity.…”

Musashi expression in intestinal stem cells attenuates radiation-induced decline in intestinal permeability and survival in Drosophila

“…Immunohistochemistry and histology. Immunohistochemistry and histology were performed using protocol previously described 117,118 . For immunohistochemistry, flies were dissected in PEM (100 mM Pipes, 2 mM EGTA and 1 mM MgSO4).…”

Glia-neuron signaling mediated by two different BMP ligands impacts synaptic growth

“…Neuron-glia interactions in a Drosophila Parkinson’s model have implicated the activation of BMP signaling in glia of the larval brain in the age-dependent neurodegeneration of DA neurons associated with LRRK2 overexpression (Maksoud et al 2019). Similarly, in a paraquat-induced model of Parkinson’s disease, the knockdown of Mad in glia was found to protect against the toxic effects of paraquat on DA neuron survival and adult longevity (Maksoud et al 2019).…”