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

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...

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Detalles Bibliográficos
Autores principales: Maksoud, Elie, Liao, Edward H., Haghighi, A. Pejmun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474846/
https://www.ncbi.nlm.nih.gov/pubmed/30759389
http://dx.doi.org/10.1016/j.celrep.2019.01.077
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author Maksoud, Elie
Liao, Edward H.
Haghighi, A. Pejmun
author_facet Maksoud, Elie
Liao, Edward H.
Haghighi, A. Pejmun
author_sort Maksoud, Elie
collection PubMed
description 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.
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spelling pubmed-64748462019-04-20 A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration Maksoud, Elie Liao, Edward H. Haghighi, A. Pejmun Cell Rep Article 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. 2019-02-12 /pmc/articles/PMC6474846/ /pubmed/30759389 http://dx.doi.org/10.1016/j.celrep.2019.01.077 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Maksoud, Elie
Liao, Edward H.
Haghighi, A. Pejmun
A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration
title A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration
title_full A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration
title_fullStr A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration
title_full_unstemmed A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration
title_short A Neuron-Glial Trans-Signaling Cascade Mediates LRRK2-Induced Neurodegeneration
title_sort neuron-glial trans-signaling cascade mediates lrrk2-induced neurodegeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474846/
https://www.ncbi.nlm.nih.gov/pubmed/30759389
http://dx.doi.org/10.1016/j.celrep.2019.01.077
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