Tau is a microtubule associated protein (MAP) primarily expressed in neurons that has traditionally been thought to promote microtubule assembly and stability in the axon. However, recent in vitro motility experiments have also demonstrated that tau is a potent inhibitor of processive kinesin movement along microtubules. These results present an interesting paradox, namely - how can kinesin processively transport its cargo along micro tubules in the presence of tau, which is highly expressed in neurons and localized to the axon? The answer to this question has important implications for axonal transport, a critical process in neurons required for the efficient delivery of organelles, proteins, nucleic acids, and small molecules synthesized in the cell body to their site of function in distal regions of the axon. Defects in anyone of the protein components in the axonal transport machinery, which includes microtubules, members of the kinesin superfamily of motor proteins, a variety of adapter molecules that link kinesin to its intracellular cargo, and MAPs such as tau, result in serious and often lethal neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and ALS. We propose two interrelated hypotheses regarding the interaction of tau and microtubules in regulating kinesin motility during axonal transport: 1.) Tau bound to different sites on microtubules have distinct functions, and only tau bound to the exterior site on polymerized microtubules inhibits kinesin motility. 2.) Specific posttranslational modifications of tubulin such as acetylation promote the binding and motility of kinesin in neuronal axons even in the presence of tau.
Defects in any one of the protein components in the axonal transport machinery, including MAPs such as tau, result in serious and often lethal neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and ALS. Thus understanding tau's role in modulating kinesin motility in the neuron is imperative to elucidating the molecular mechanisms of axonal transport in both normal and pathological states.
| Thompson, Andrew R; Hoeprich, Gregory J; Berger, Christopher L (2013) Single-molecule motility: statistical analysis and the effects of track length on quantification of processive motion. Biophys J 104:2651-61 |
| McVicker, Derrick P; Chrin, Lynn R; Berger, Christopher L (2011) The nucleotide-binding state of microtubules modulates kinesin processivity and the ability of Tau to inhibit kinesin-mediated transport. J Biol Chem 286:42873-80 |
| Yengo, Christopher M; Berger, Christopher L (2010) Fluorescence anisotropy and resonance energy transfer: powerful tools for measuring real time protein dynamics in a physiological environment. Curr Opin Pharmacol 10:731-7 |
