NeuralCipher Research overview
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Deregulated microtubules are common defects associated with neurodegenerative diseases. Recent cryo-electron microscopy studies in cell lines overexpressing Parkinson's disease-associated LRRK2 suggest microtubule surfaces may regulate kinase activity by stabilizing different LRRK2 conformations. In macrophages with high endogenous LRRK2 expression, we find that nocodazole treatment destabilizes microtubules and impairs LRRK2-mediated Rab phosphorylation. GTP supplementation restores nocodazole-reduced Rab phosphorylation, linking LRRK2 kinase action to cellular GTP levels. Chemical microtubule stabilization, and kinetically trapping LRRK2 to microtubule surfaces, has negligible effects on Rab phosphorylation. In contrast, trapping LRRK2 to LAMP1-positive membranes upregulates LRRK2-mediated Rab phosphorylation. Proximity-labeling proteomics and colocalization studies show that LRRK2 robustly interacts with both polymerized and free tubulin transiently and independently of LRRK2 kinase activity. Endogenous LRRK2 complexed with type I inhibitors in neurons and macrophages fails to stably interact with microtubules, whereas bulky N-terminal tags fused to LRRK2 promotes stable microtubule binding in cell lines. Collectively, these results show that tubulin isoforms and microtubules are transient LRRK2-interacting proteins non-essential for LRRK2-mediated Rab phosphorylation.
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