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Int. J. Mol. Sci. 2019, 20(3), 748; https://doi.org/10.3390/ijms20030748

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

1
Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Via Galvani 31, 39100 Bolzano, Italy
2
Department of Cellular, Computational and Integrative Biology and Dulbecco Telethon Institute, University of Trento, via Sommarive 9, 38123 Povo, Italy
3
Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Straße 1, 23562 Lübeck, Germany
4
Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
These authors contributed equally.
*
Author to whom correspondence should be addressed.
Received: 30 November 2018 / Revised: 31 January 2019 / Accepted: 4 February 2019 / Published: 11 February 2019
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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Abstract

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. View Full-Text
Keywords: Parkin; apoptosis-inducing factor; cell death; neurodegeneration; Parkinson’s disease Parkin; apoptosis-inducing factor; cell death; neurodegeneration; Parkinson’s disease
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Guida, M.; Zanon, A.; Montibeller, L.; Lavdas, A.A.; Ladurner, J.; Pischedda, F.; Rakovic, A.; Domingues, F.S.; Piccoli, G.; Klein, C.; Pramstaller, P.P.; Hicks, A.A.; Pichler, I. Parkin Interacts with Apoptosis-Inducing Factor and Interferes with Its Translocation to the Nucleus in Neuronal Cells. Int. J. Mol. Sci. 2019, 20, 748.

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