17 Oct 2004

Microtubule affinity regulating kinases (MARKs) regulate transport along axonal microtubules by pulling microtubule-associated proteins, including tau, off the tracks to allow cargo-carrying "motors" to pass, according to a paper published in the 11 October issue of the Journal of Cell Biology. Eva-Maria Mandelkow, Eckard Mandelkow and colleagues of the Max-Planck Unit for Structural Molecular Biology in Hamburg, Germany, suggest that this regulatory mechanism might be called into action to prevent Aβ production in Alzheimer disease.

Microtubule-associated proteins (MAPs), notably tau, stabilize microtubules, ensuring that distal cell processes receive needed supplies and that other materials, such as endocytosed molecules, are transported back to the soma. But it also appears that MAPs can get in the way of the motors kinesin and dynein as they move their cargo along the microtubules. Overexpression of tau, for example, has been shown to inhibit traffic in both directions, but particularly away from the soma (see ARF related news story). This phenomenon has even been used to link the amyloid sphere of Alzheimer research to the tau sphere, in that tau interruption of axonal transport can keep APP from being transported to its destination at the ends of axons (for more discussion on the intersection of tau and APP in the regulation of microtubules, see Peter Davies's meeting report).

Could posttranslational modification of MAPs, therefore, control the rate of transport along microtubules? The authors investigated this possibility in different cell models, focusing in particular on MARK (a homologue of the invertebrate Par1). Among the various kinases involved in phosphorylating tau in Alzheimer disease, MARK has been proposed as the one that initiates the process (see ARF related news story).

First author Eva-Maria Mandelkow and colleagues provide evidence from CHO cell studies that MAPs of different varieties have essentially similar inhibitory effects on transport along microtubules. They further found that the MARK2 pulls these MAPs off the microtubules, allowing more efficient passage along the tracks. Another set of experiments, this time using retinal ganglion cells, showed that microtubule transport of mitochondria and APP-containing vesicles out to the axons was inhibited by transfecting the neurons with tau, but cotransfection with MARK2 rescued the transport of both organelles. The researchers also showed that phosphorylation at tau KXGS motifs (also found in other MAPs) was the critical step in this rescue—mutant tau with corrupted KXGS motifs was impervious to MARK2.

Mandelkow and colleagues suggest that a great deal remains to be worked out, including the different ways in which tau can be phosphorylated by different kinases, and the different effects this might have vis-à-vis microtubule binding. But the authors do speculate that if tau were to interfere with transport of APP from the soma, it might lead to more intracellular cleavage of APP, resulting in more toxic Aβ species. How are we to square that proposition with the fact that AD is characterized by hyperphosphorylated tau, which ought to dissociate from microtubules and facilitate APP transport to the far reaches of cellular processes? Mandelkow and colleagues suggest that this is a compensatory response. "Thus, the early phosphorylation of tau at KXGS motifs observed in Alzheimer's disease could be seen as the cell's defense strategy to keep traffic pathways open and to reduce the generation of toxic byproducts," they write.—Hakon Heimer