Microtubule polarity flaws as a treatable driver of neurodegeneration

Microtubule disruption is a common downstream mechanism leading to axonal degeneration in a number of neurological diseases. To date, most studies on this topic have focused on the loss of microtubule mass from the axon, as well as changes in the stability properties of the microtubules and/or their tubulin composition. Here we posit corruption of the normal pattern of microtubule polarity orientation as an underappreciated and yet treatable contributor to axonal degeneration. We include computational modeling to fortify the rigor of our considerations. Our simulations demonstrate that even a small deviation from the usual polarity pattern of axonal microtubules is detrimental to motor-based trafficking of organelles and other intracellular cargo. Additional modeling predicts that axons with such deviations will exhibit significantly reduced speed and reli-ability of organelle transport, and that localized clusters of wrongly oriented microtubules will result in traffic jams of accumulated organelles.