Parkinson’s drug reshapes cell architecture unexpectedly
A much-discussed Parkinson’s inhibitor does something unexpected: depending on how the molecule approaches its target, it dramatically rearranges the internal architecture of cells. That has implications for how the drug can safely be used.
In familial and some sporadic cases of Parkinson’s disease, a protein called LRRK2 plays a central role. LRRK2 is a kinase, meaning it activates other proteins by attaching a phosphate group to them. In certain inherited forms of Parkinson’s, LRRK2 is overactive, disrupting cellular logistics and the clearance of damaged material. Inhibitors of LRRK2 have therefore been in development as a potential Parkinson’s therapy for years.
Researchers used cryo-electron tomography to examine what happens inside living cells when LRRK2 is inhibited. They tested two types of inhibitors: type I and type II. The study, published in eLife, shows that type I inhibitors cause LRRK2 to stack around microtubules, the cell’s internal transport tubes. This leads to bundling of those tubes, potentially disrupting cellular transport. Type II inhibitors cause far less of this effect.
Structure makes the difference
Microtubules are essential for transporting proteins, organelles, and signals within neurons. When LRRK2 assembles into large filaments around them, cellular logistics can be disrupted, precisely the type of damage already seen in Parkinson’s disease. Whether this effect occurs the same way in humans has not yet been studied. But the findings suggest that the choice of inhibitor type has consequences beyond kinase activity alone.
The researchers also succeeded in building a full 3D model of the LRRK2 protein in its closed conformation within its cellular environment. This is valuable for developing more precisely targeted inhibitors going forward.
Early-stage but relevant
This research was conducted in cell lines, not in patients. What type I inhibitors do in a human nervous system over the long term is unknown. The researchers call for greater attention to this distinction in the further clinical development of LRRK2 inhibitors. From a longevity perspective, this matters: LRRK2 activity is also linked to neuronal aging independently of a Parkinson’s diagnosis.
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