GTP binding regulates cellular localization of Parkinson's disease-associated LRRK2

Marian Blanca Ramírez, Antonio Jesús Lara Ordóñez, Elena Fdez, Jesús Madero-Pérez, Adriano Gonnelli, Matthieu Drouyer, Marie Christine Chartier-Harlin, Jean Marc Taymans, Luigi Bubacco, Elisa Greggio, Sabine Hilfiker

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise the most common cause of familial Parkinson's disease (PD), and sequence variants modify risk for sporadic PD. Previous studies indicate that LRRK2 interacts with microtubules (MTs) and alters MT-mediated vesicular transport processes. However, the molecular determinants within LRRK2 required for such interactions have remained unknown. Here, we report that most pathogenic LRRK2 mutants cause relocalization of LRRK2 to filamentous structures which colocalize with a subset of MTs, and an identical relocalization is seen upon pharmacological LRRK2 kinase inhibition. The pronounced colocalization with MTs does not correlate with alterations in LRRK2 kinase activity, but rather with increased GTP binding. Synthetic mutations which impair GTP binding, as well as LRRK2 GTP-binding inhibitors profoundly interfere with the abnormal localization of both pathogenic mutant as well as kinase-inhibited LRRK2. Conversely, addition of a non-hydrolyzable GTP analog to permeabilized cells enhances the association of pathogenic or kinase-inhibited LRRK2 with MTs. Our data elucidate the mechanism underlying the increased MT association of select pathogenic LRRK2 mutants or of pharmacologically kinase-inhibited LRRK2, with implications for downstreamMT-mediated transport events.

Original languageEnglish (US)
Pages (from-to)2747-2767
Number of pages21
JournalHuman molecular genetics
Volume26
Issue number14
DOIs
StatePublished - Jul 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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