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The role of LRRK2 at the cytoskeleton
The interaction of LRRK2 with microtubules has pathogenic relevance, since mutations in PARK8 segregating with Parkinson’s disease reduce neurite outgrowth and cause an accumulation of hyperphosphorylated tau. In turn, defective post-translational modifications of tubulin and microtubule-associated proteins are known to cause alterations in the dynamic instability of microtubules, leading to aberrant axonal transport, synaptic dysfunction and axonal degeneration. We found a selective interaction between LRRK2 and two β-tubulin isoforms. This interaction is conferred by the LRRK2 Roc GTPase domain and the β-tubulin C-termini. It is dependent on guanidine nucleotide binding and Roc domain autophosphorylation and disrupted by the pathogenic PARK8 mutation R1441G. We were also able to demonstrate the specificity of the LRRK2 β-tubulin interaction and our results suggest the possibility that phosphorylation of β-tubulin isoforms could hinder LRRK2-tubulin interactions. This suggests further that reciprocal mutations affecting C-terminal residues of β-tubulin isoforms could disrupt interactions with LRRK2 without compromising integration into microtubules. On-going work has also demonstrated that LRRK2 co-localises with highly dynamic cytoskeletal structures in dopaminergic cells, including growth cones.
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