Short- and Long-Term Effects of LRRK2 on Axon and Dendrite Growth

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) underlie an autosomal-dominant form of Parkinson's disease (PD) that is clinically indistinguishable from idiopathic PD. The function of LRRK2 is not well understood, but it has become widely accepted that LRRK2 levels or its kinase activity, which is increased by the most commonly observed mutation (G2019S), regulate neurite growth. However, growth has not been measured; it is not known whether mean differences in length correspond to altered rates of growth or retraction, whether axons or dendrites are impacted differentially or whether effects observed are transient or sustained. To address these questions, we compared several developmental milestones in neurons cultured from mice expressing bacterial artificial chromosome transgenes encoding mouse wildtype-LRRK2 or mutant LRRK2-G2019S, Lrrk2 knockout mice and non-transgenic mice. Over the course of three weeks of development on laminin, the data show a sustained, negative effect of LRRK2-G2019S on dendritic growth and arborization, but counter to expectation, dendrites from Lrrk2 knockout mice do not elaborate more rapidly. In contrast, young neurons cultured on a slower growth substrate, poly-L-lysine, show significantly reduced axonal and dendritic motility in Lrrk2 transgenic neurons and significantly increased motility in Lrrk2 knockout neurons with no significant changes in length. Our findings support that LRRK2 can regulate patterns of axonal and dendritic growth, but they also show that effects vary depending on growth substrate and stage of development. Such predictable changes in motility can be exploited in LRRK2 bioassays and guide exploration of LRRK2 function in vivo.

Leucine‐rich repeat kinase 2 interacts with p21‐activated kinase 6 to control neurite complexity in mammalian brain

“…; Sepulveda et al . ). To investigate a putative role of LRRK2 and PAK6 in regulating neuronal morphology in vivo , we measured the effect of PAK6 expression on neurite length in LRRK2 wild‐type versus knock‐out mouse striatum.…”

Altered Development of Synapse Structure and Function in Striatum Caused by Parkinson's Disease-Linked LRRK2-G2019S Mutation

“…Several laboratories have shown that overexpression of LRRK2-G2019S can reduce neurite growth (MacLeod et al, 2006;Parisiadou et al, 2009;Dächsel et al, 2010;Ramonet et al, 2011;Winner et al, 2011;Sepulveda et al, 2013). However, this phenotype appears to be attributable at least in part to overexpression (Skibinski et al, 2014) because changes in neither dendrite length nor synapse density have been reported in cultured hippocampal or cortical neurons expressing physiological levels of LRRK2-G2019S (Dächsel et al, 2010;Beccano-Kelly et al, 2014), consistent with results reported here.…”

Increased peripheral inflammation in asymptomatic leucine‐rich repeat kinase 2 mutation carriers

“…This suggests that the onset of PD exacerbates the effect of the mutation. Intriguingly, features of the G2019S mutation in cell culture and animal models are impaired neurite outgrowth, neurite branching complexity, and neurogenesis . Being potent trophic factors, both PDGF and VEGF are involved in promoting neurite outgrowth and branching suggesting that the elevated levels in G2019S PD patients may be compensatory for the negative effects of the mutation.…”