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.

The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1 / M. Perez Carrion, F. Pischedda, A. Biosa, I. Russo, L. Straniero, L. Civiero, M. Guida, C.J. Gloeckner, N. Ticozzi, C. Tiloca, C. Mariani, G. Pezzoli, S. Duga, I. Pichler, L. Pan, J.E. Landers, E. Greggio, M.W. Hess, S. Goldwurm, G. Piccoli. - In: FRONTIERS IN MOLECULAR NEUROSCIENCE. - ISSN 1662-5099. - 11(2018 Feb 28).

The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1

F. Pischedda;L. Straniero;N. Ticozzi;C. Tiloca;S. Duga;
2018

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.
DRP1; LRRK2; Parkinson’s disease; mitochondria; protein interaction
Settore MED/26 - Neurologia
28-feb-2018
Article (author)
File in questo prodotto:
File Dimensione Formato  
fnmol-11-00064 (1).pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 6.42 MB
Formato Adobe PDF
6.42 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/618084
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 30
  • ???jsp.display-item.citation.isi??? 16
social impact