The transport of mitochondria (red) is restored by MARK (top cell) in cells that have high tau.

Microtubule-associated proteins (MAPs) stabilize the filaments to which they are attached. But they are also a hindrance to microtubule-based motors trying to move themselves and their cargos down the tracks. Now, on page 99, Mandelkow et al. show that some kinases that phosphorylate MAPs in their microtubule-binding domains clear the path for motors. Alterations in the balance of this system may be an early defect in Alzheimer's disease.

Elevated levels of the neuronal MAP tau were previously shown to inhibit axon-directed transport. The group finds microtubule-based traffic is also inhibited by other MAPs, then tests what happens when MAPs are released from microtubules by phosphorylation.

One kinase that regulates this interaction is MARK, which phosphorylates tau, MAP2, and MAP4. Also known as Par-1, MARK is needed for cell polarity and neurite outgrowth. MARK is now shown to relieve the transport inhibition caused by MAPs. After slightly elevating the levels of MARK to avoid stripping microtubules of MAPs (which would thereby destabilize the filaments and stop traffic altogether), the authors show that vesicles and organelles moved longer distances at a stretch and changed direction less frequently, thus moving more efficiently.

In neurons, the end result of MARK activity is the renewal of axonal-directed transport. High levels of tau, which are seen in Alzheimer's, may inhibit transport. As a result, neurons degenerate because their axons are not maintained; they lack mitochondria and peroxisomes and thus suffer from energy deprivation and oxidative stress. Traffic inhibition also backs up the amyloid precursor protein, which could lead to enhanced processing and thus accumulation of the toxic Aβ peptide in the neuron.

MARK can prevent these problems by restoring transport, but too much MARK is also dangerous because tau is needed to stabilize the microtubule filaments. Slight imbalances in either direction could thus lead to neurodegeneration.