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Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells

Mutations in the PRKN gene (encoding parkin) have been linked to the most frequent known cause of recessive Parkinson’s disease (PD), and parkin dysfunction represents a risk factor for sporadic PD. Parkin is widely neuroprotective through different cellular pathways, as it protects dopaminergic neu...

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Autores principales: Guida, Marianna, Zanon, Alessandra, Montibeller, Luigi, Lavdas, Alexandros A., Ladurner, Judith, Pischedda, Francesca, Rakovic, Aleksandar, Domingues, Francisco S., Piccoli, Giovanni, Klein, Christine, Pramstaller, Peter P., Hicks, Andrew A., Pichler, Irene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386878/
https://www.ncbi.nlm.nih.gov/pubmed/30754623
http://dx.doi.org/10.3390/ijms20030748
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author Guida, Marianna
Zanon, Alessandra
Montibeller, Luigi
Lavdas, Alexandros A.
Ladurner, Judith
Pischedda, Francesca
Rakovic, Aleksandar
Domingues, Francisco S.
Piccoli, Giovanni
Klein, Christine
Pramstaller, Peter P.
Hicks, Andrew A.
Pichler, Irene
author_facet Guida, Marianna
Zanon, Alessandra
Montibeller, Luigi
Lavdas, Alexandros A.
Ladurner, Judith
Pischedda, Francesca
Rakovic, Aleksandar
Domingues, Francisco S.
Piccoli, Giovanni
Klein, Christine
Pramstaller, Peter P.
Hicks, Andrew A.
Pichler, Irene
author_sort Guida, Marianna
collection PubMed
description Mutations in the PRKN gene (encoding parkin) have been linked to the most frequent known cause of recessive Parkinson’s disease (PD), and parkin dysfunction represents a risk factor for sporadic PD. Parkin is widely neuroprotective through different cellular pathways, as it protects dopaminergic neurons from apoptosis in a series of cellular and animal models of PD. The mitochondrial protein apoptosis-inducing factor (AIF) is an important cell death effector, which, upon cellular stress in many paradigms, is redistributed from the mitochondria to the nucleus to function as a proapoptotic factor, mostly independent of caspase activity, while in normal mitochondria it functions as an antiapoptotic factor. AIF is known to participate in dopaminergic neuron loss in experimental PD models and in patients with PD. We, therefore, investigated possible crosstalk between parkin and AIF. By using immunoprecipitation and proximity ligation assays, we demonstrated a physical interaction between the two proteins. Nuclear AIF translocation was significantly reduced by parkin expression in neuroblastoma SH-SY5Y cells after exposure to an apoptogenic stimulus. These results were confirmed in primary murine cortical neurons, which showed a higher nuclear translocation of AIF in parkin-deficient neurons upon an excitotoxic stimulus. Our results indicate that the interaction of parkin with AIF interferes with the nuclear translocation of AIF, which might contribute to the neuroprotective activity of parkin.
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spelling pubmed-63868782019-02-27 Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells Guida, Marianna Zanon, Alessandra Montibeller, Luigi Lavdas, Alexandros A. Ladurner, Judith Pischedda, Francesca Rakovic, Aleksandar Domingues, Francisco S. Piccoli, Giovanni Klein, Christine Pramstaller, Peter P. Hicks, Andrew A. Pichler, Irene Int J Mol Sci Communication Mutations in the PRKN gene (encoding parkin) have been linked to the most frequent known cause of recessive Parkinson’s disease (PD), and parkin dysfunction represents a risk factor for sporadic PD. Parkin is widely neuroprotective through different cellular pathways, as it protects dopaminergic neurons from apoptosis in a series of cellular and animal models of PD. The mitochondrial protein apoptosis-inducing factor (AIF) is an important cell death effector, which, upon cellular stress in many paradigms, is redistributed from the mitochondria to the nucleus to function as a proapoptotic factor, mostly independent of caspase activity, while in normal mitochondria it functions as an antiapoptotic factor. AIF is known to participate in dopaminergic neuron loss in experimental PD models and in patients with PD. We, therefore, investigated possible crosstalk between parkin and AIF. By using immunoprecipitation and proximity ligation assays, we demonstrated a physical interaction between the two proteins. Nuclear AIF translocation was significantly reduced by parkin expression in neuroblastoma SH-SY5Y cells after exposure to an apoptogenic stimulus. These results were confirmed in primary murine cortical neurons, which showed a higher nuclear translocation of AIF in parkin-deficient neurons upon an excitotoxic stimulus. Our results indicate that the interaction of parkin with AIF interferes with the nuclear translocation of AIF, which might contribute to the neuroprotective activity of parkin. MDPI 2019-02-11 /pmc/articles/PMC6386878/ /pubmed/30754623 http://dx.doi.org/10.3390/ijms20030748 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Guida, Marianna
Zanon, Alessandra
Montibeller, Luigi
Lavdas, Alexandros A.
Ladurner, Judith
Pischedda, Francesca
Rakovic, Aleksandar
Domingues, Francisco S.
Piccoli, Giovanni
Klein, Christine
Pramstaller, Peter P.
Hicks, Andrew A.
Pichler, Irene
Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells
title Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells
title_full Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells
title_fullStr Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells
title_full_unstemmed Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells
title_short Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells
title_sort parkin interacts with apoptosis-inducing factor and interferes with its translocation to the nucleus in neuronal cells
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386878/
https://www.ncbi.nlm.nih.gov/pubmed/30754623
http://dx.doi.org/10.3390/ijms20030748
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