LRRK2 Parkinson disease mutations enhance its microtubule association.

Hum Mol Genet 2012 Feb 11;21(4):890-9. Epub 2011 Nov 11.

Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddr526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263991PMC
February 2012
23 Reads

Publication Analysis

Top Keywords

lrrk2
9
intact kinase
8
lrrk2-related neurodegeneration
8
microtubule association
8
kinase function
8
lrrk2 mutants
8
parkinson disease
8
causing form
4
wd40 domain
4
oligomerization causing
4
domain linking
4
lrrk2 oligomerization
4
transfections cell
4
filamentous structures
4
structures transfections
4
enhance lrrk2
4
form filamentous
4
function wd40
4
linking microtubule
4
binding neurodegeneration
4

Similar Publications