title: LRRK2 Parkinson disease mutations enhance its microtubule association.
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.
authors.affiliation: Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Kett
authors.forename: Daniela
authors.initials: D
authors.lastname: Boassa
authors.forename: Cherry Cheng-Ying
authors.initials: CC
authors.lastname: Ho
authors.forename: Hardy J
authors.initials: HJ
authors.lastname: Rideout
authors.forename: Junru
authors.initials: J
authors.lastname: Hu
authors.forename: Masako
authors.initials: M
authors.lastname: Terada
authors.forename: Mark
authors.initials: M
authors.lastname: Ellisman
authors.forename: William T
authors.initials: WT
authors.lastname: Dauer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D050505:Mutant Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
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