LRRK2 Parkinson disease mutations enhance its microtubule association

Lauren R. Kett, Daniela Boassa, Cherry Cheng Ying Ho, Hardy J. Rideout, Junru Hu, Masako Terada, Mark Ellisman, William T. Dauer

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic causes of Parkinson disease (PD) and genome-wide association studies identify LRRK2 sequence variants as risk factors for sporadic PD. Intact kinase function appears critical for the toxicity of LRRK2 PD mutants, yet our understanding of how LRRK2 causes neurodegeneration remains limited. We find that most LRRK2 PD mutants abnormally enhance LRRK2 oligomerization, causing it to form filamentous structures in transfections of cell lines or primary neuronal cultures. Strikingly, ultrastructural analyses, including immuno-electron microscopy and electron microscopic tomography, demonstrate that these filaments consist of LRRK2 recruited onto part of the cellular microtubule network in a well-ordered, periodic fashion. Like LRRK2-related neurodegeneration, microtubule association requires intact kinase function and the WD40 domain, potentially linking microtubule binding and neurodegeneration. Our observations identify a novel effect of LRRK2 PD mutations and highlight a potential role for microtubules in the pathogenesis of LRRK2-related neurodegeneration.

Original languageEnglish (US)
Article numberddr526
Pages (from-to)890-899
Number of pages10
JournalHuman molecular genetics
Volume21
Issue number4
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Kett, L. R., Boassa, D., Ho, C. C. Y., Rideout, H. J., Hu, J., Terada, M., Ellisman, M., & Dauer, W. T. (2012). LRRK2 Parkinson disease mutations enhance its microtubule association. Human molecular genetics, 21(4), 890-899. [ddr526]. https://doi.org/10.1093/hmg/ddr526