TY - JOUR
T1 - The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1
AU - Perez Carrion, Maria
AU - Pischedda, Francesca
AU - Biosa, Alice
AU - Russo, Isabella
AU - Straniero, Letizia
AU - Civiero, Laura
AU - Guida, Marianna
AU - Gloeckner, Christian J
AU - Ticozzi, Nicola
AU - Tiloca, Cinzia
AU - Mariani, Claudio
AU - Pezzoli, Gianni
AU - Duga, Stefano
AU - Pichler, Irene
AU - Pan, Lifeng
AU - Landers, John E
AU - Greggio, Elisa
AU - Hess, Michael W
AU - Goldwurm, Stefano
AU - Piccoli, Giovanni
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.3389/fnmol.2018.00064
DO - 10.3389/fnmol.2018.00064
M3 - Article
C2 - 29541021
VL - 11
SP - 64
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
SN - 1662-5099
ER -