Frontiers in Molecular Neuroscience (Feb 2018)
The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1
- Maria Perez Carrion,
- Francesca Pischedda,
- Alice Biosa,
- Isabella Russo,
- Letizia Straniero,
- Laura Civiero,
- Marianna Guida,
- Christian J. Gloeckner,
- Christian J. Gloeckner,
- Nicola Ticozzi,
- Nicola Ticozzi,
- Cinzia Tiloca,
- Cinzia Tiloca,
- Claudio Mariani,
- Gianni Pezzoli,
- Stefano Duga,
- Stefano Duga,
- Irene Pichler,
- Lifeng Pan,
- John E. Landers,
- Elisa Greggio,
- Michael W. Hess,
- Stefano Goldwurm,
- Stefano Goldwurm,
- Giovanni Piccoli
Affiliations
- Maria Perez Carrion
- Dulbecco Telethon Institute, CIBIO, Università degli Studi di Trento, Trento, Italy
- Francesca Pischedda
- Dulbecco Telethon Institute, CIBIO, Università degli Studi di Trento, Trento, Italy
- Alice Biosa
- Dipartimento di Biologia, Università di Padova, Padova, Italy
- Isabella Russo
- Dipartimento di Biologia, Università di Padova, Padova, Italy
- Letizia Straniero
- Humanitas Clinical and Research Center, Milan, Italy
- Laura Civiero
- Dipartimento di Biologia, Università di Padova, Padova, Italy
- Marianna Guida
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy
- Christian J. Gloeckner
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
- Christian J. Gloeckner
- Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany
- Nicola Ticozzi
- Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- Nicola Ticozzi
- Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, Milan, Italy
- Cinzia Tiloca
- Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
- Cinzia Tiloca
- Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, Milan, Italy
- Claudio Mariani
- Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy
- Gianni Pezzoli
- Parkinson Institute, ASST Gaetano Pini-CTO, Milan, Italy
- Stefano Duga
- Humanitas Clinical and Research Center, Milan, Italy
- Stefano Duga
- 0Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Irene Pichler
- Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy
- Lifeng Pan
- 1Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
- John E. Landers
- 2Department of Neurology, University of Massachusetts Medical School, University of Massachusetts, Worcester, MA, United States
- Elisa Greggio
- Dipartimento di Biologia, Università di Padova, Padova, Italy
- Michael W. Hess
- 3Division of Histology and Embryology, Innsbruck Medical University, Innsbruck, Austria
- Stefano Goldwurm
- Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, Milan, Italy
- Stefano Goldwurm
- 4Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy
- Giovanni Piccoli
- Dulbecco Telethon Institute, CIBIO, Università degli Studi di Trento, Trento, Italy
- DOI
- https://doi.org/10.3389/fnmol.2018.00064
- Journal volume & issue
-
Vol. 11
Abstract
Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson’s disease (PD). LRRK2 is a complex protein that consists of multiple domains, including 13 putative armadillo-type repeats at the N-terminus. In this study, we analyzed the functional and molecular consequences of a novel variant, E193K, identified in an Italian family. E193K substitution does not influence LRRK2 kinase activity. Instead it affects LRRK2 biochemical properties, such as phosphorylation at Ser935 and affinity for 14-3-3ε. Primary fibroblasts obtained from an E193K carrier demonstrated increased cellular toxicity and abnormal mitochondrial fission upon 1-methyl-4-phenylpyridinium treatment. We found that E193K alters LRRK2 binding to DRP1, a crucial mediator of mitochondrial fission. Our data support a role for LRRK2 as a scaffolding protein influencing mitochondrial fission.
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