A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway

Abstract In experimental models, both in vivo and cellular, over-expression of Parkinson’s linked mutant leucine-rich repeat kinase 2 (LRRK2) is sufficient to induce neuronal death. While several cell death associated proteins have been linked to LRRK2, either as protein interactors or as putative s...

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Autores principales:	Nasia Antoniou, Dimitrios Vlachakis, Anna Memou, Emmanouela Leandrou, Polytimi-Eleni Valkimadi, Katerina Melachroinou, Diane B. Re, Serge Przedborski, William T. Dauer, Leonidas Stefanis, Hardy J. Rideout
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/023f75cba7e141e794a505571ddc8b16
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spelling	oai:doaj.org-article:023f75cba7e141e794a505571ddc8b162021-12-02T16:08:15ZA motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway10.1038/s41598-018-21931-82045-2322https://doaj.org/article/023f75cba7e141e794a505571ddc8b162018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21931-8https://doaj.org/toc/2045-2322Abstract In experimental models, both in vivo and cellular, over-expression of Parkinson’s linked mutant leucine-rich repeat kinase 2 (LRRK2) is sufficient to induce neuronal death. While several cell death associated proteins have been linked to LRRK2, either as protein interactors or as putative substrates, characterization of the neuronal death cascade remains elusive. In this study, we have mapped for the first time the domain within LRRK2 that mediates the interaction with FADD, thereby activating the molecular machinery of the extrinsic death pathway. Using homology modeling and molecular docking approaches, we have identified a critical motif within the N-terminal armadillo repeat region of LRRK2. Moreover, we show that co-expression of fragments of LRRK2 that contain the FADD binding motif, or deletion of this motif itself, blocks the interaction with FADD, and is neuroprotective. We further demonstrate that downstream of FADD, the mitochondrial proteins Bid and Bax are recruited to the death cascade and are necessary for neuronal death. Our work identifies multiple novel points within neuronal death signaling pathways that could potentially be targeted by candidate therapeutic strategies and highlight how the extrinsic pathway can be activated intracellularly in a pathogenic context.Nasia AntoniouDimitrios VlachakisAnna MemouEmmanouela LeandrouPolytimi-Eleni ValkimadiKaterina MelachroinouDiane B. ReSerge PrzedborskiWilliam T. DauerLeonidas StefanisHardy J. RideoutNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-17 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nasia Antoniou Dimitrios Vlachakis Anna Memou Emmanouela Leandrou Polytimi-Eleni Valkimadi Katerina Melachroinou Diane B. Re Serge Przedborski William T. Dauer Leonidas Stefanis Hardy J. Rideout A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway
description	Abstract In experimental models, both in vivo and cellular, over-expression of Parkinson’s linked mutant leucine-rich repeat kinase 2 (LRRK2) is sufficient to induce neuronal death. While several cell death associated proteins have been linked to LRRK2, either as protein interactors or as putative substrates, characterization of the neuronal death cascade remains elusive. In this study, we have mapped for the first time the domain within LRRK2 that mediates the interaction with FADD, thereby activating the molecular machinery of the extrinsic death pathway. Using homology modeling and molecular docking approaches, we have identified a critical motif within the N-terminal armadillo repeat region of LRRK2. Moreover, we show that co-expression of fragments of LRRK2 that contain the FADD binding motif, or deletion of this motif itself, blocks the interaction with FADD, and is neuroprotective. We further demonstrate that downstream of FADD, the mitochondrial proteins Bid and Bax are recruited to the death cascade and are necessary for neuronal death. Our work identifies multiple novel points within neuronal death signaling pathways that could potentially be targeted by candidate therapeutic strategies and highlight how the extrinsic pathway can be activated intracellularly in a pathogenic context.
format	article
author	Nasia Antoniou Dimitrios Vlachakis Anna Memou Emmanouela Leandrou Polytimi-Eleni Valkimadi Katerina Melachroinou Diane B. Re Serge Przedborski William T. Dauer Leonidas Stefanis Hardy J. Rideout
author_facet	Nasia Antoniou Dimitrios Vlachakis Anna Memou Emmanouela Leandrou Polytimi-Eleni Valkimadi Katerina Melachroinou Diane B. Re Serge Przedborski William T. Dauer Leonidas Stefanis Hardy J. Rideout
author_sort	Nasia Antoniou
title	A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway
title_short	A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway
title_full	A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway
title_fullStr	A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway
title_full_unstemmed	A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway
title_sort	motif within the armadillo repeat of parkinson’s-linked lrrk2 interacts with fadd to hijack the extrinsic death pathway
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/023f75cba7e141e794a505571ddc8b16
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A motif within the armadillo repeat of Parkinson’s-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway

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