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.

Ser 1292 Autophosphorylation Is an Indicator of LRRK2 Kinase Activity and Contributes to the Cellular Effects of PD Mutations

“…Recently, it was suggested that LRRK2 PD mutations cause defects in nuclear envelope organization (34). It was previously observed that LRRK2 PD mutant proteins accumulate on microtubules in primary neurons (35). In addition, several studies have implicated LRRK2 in the autophagy pathway (36)(37)(38)(39).…”

Changes in actin dynamics and F-actin structure both in synaptoneurosomes of LRRK2(R1441G) mutant mice and in primary human fibroblasts of LRRK2(G2019S) mutation carriers

“…Yet filopodial outgrowth is not just a function of actin dynamics and stability but it is also tightly controlled by the tubulin cytoskeleton. LRRK2 also directly interacts with microtubules by binding to beta-tubulin (Gandhi et al, 2008;Gillardon, 2009a;Kett et al, 2012;Law et al, 2014). The G2019S mutation in the kinase domain markedly increases LRRK2-mediated beta tubulin phosphorylation (Gillardon, 2009a).…”

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

“…Several LRRK2 mutations cause a reduction in neurite growth that is rescued by LRRK2 inhibition [37-40], suggesting that LRRK2 influences the cytoskeleton. Kett et al [41] reported that most LRRK2 mutations enhance LRRK2 oligomerization and generate microtubule-associated filamentous structures in cells. Godena et al [42] found that LRRK2 containing ROC-COR mutations (R1441C and Y1699C) mainly binds to deacetylated microtubules and that deacetylase inhibitors and tubulin acetylase block this association.…”