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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00064

The LRRK2 variant E193K prevents mitochondrial fission upon MPP+ treatment by altering LRRK2 binding to DRP1.

 Maria Perez-Carrion1, Francesca Pischedda1, Isabella Russo2,  Letizia Straniero3,  Laura Civiero2, Marianna Guida4,  Christian Johannes Gloeckner5, Nicola Ticozzi6, Cinzia Tiloca6, Claudio Mariani7, Gianni Pezzoli7, Stefano Duga3, Lifeng Pan8, John Landers9,  Elisa Greggio2,  Michael Hess10,  Stefano Goldwurm7 and  Giovanni Piccoli1*
  • 1University of Trento, Italy
  • 2Università degli Studi di Padova, Italy
  • 3Humanitas Research Hospital, Italy
  • 4EURAC research, Italy
  • 5Deutsche Zentrum für Neurodegenerative Erkrankungen (DZNE), Germany
  • 6Istituto Auxologico Italiano (IRCCS), Italy
  • 7Istituto Ortopedico Gaetano Pini, Italy
  • 8Shanghai Institute of Organic Chemistry (CAS), China
  • 9University of Massachusetts Medical School, United States
  • 10Innsbruck Medical University, Austria

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson’s disease. 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 14-3-3e. 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.

Keywords: LRRK2, DRP1, Mitochondria, Protein interaction, Parkinson’s disease

Received: 03 Nov 2017; Accepted: 15 Feb 2018.

Edited by:

Shin-ichi Hisanaga, Tokyo Metropolitan University, Japan

Reviewed by:

Luca Murru, Consiglio Nazionale Delle Ricerche (CNR), Italy
Ralf J. Braun, University of Bayreuth, Germany
Etsuro Ohta, Department of Immunology, School of Allied Health Sciences, Kitasato University, Japan  

Copyright: © 2018 Perez-Carrion, Pischedda, Russo, Straniero, Civiero, Guida, Gloeckner, Ticozzi, Tiloca, Mariani, Pezzoli, Duga, Pan, Landers, Greggio, Hess, Goldwurm and Piccoli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Giovanni Piccoli, University of Trento, Trento, Italy, giovanni.piccoli@unitn.it