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 microtubules 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 any one 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. This proposal will elucidate the mechanistic basis for isoform specific differences in Tau's ability to modulate the processive motility of the major molecular motors involved in axonal transport, including kinesin-1, kinesin-2, and kinesin-3, as well as cytoplasmic dynein. Additionally, the effects of phosphorylation of Tau at physiologically-relevant and pathogenic sites on motor protein function and microtubule organization and architecture will be examined in in vitro cellular and reconstituted protein experiments using state-of- the art single molecule imaging techniques.
Defects in any one of the protein components in the axonal transport machinery, including microtubule associated proteins 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 microtubule structure and motor protein function in the neuron is imperative to elucidating the molecular mechanisms of axonal transport in both normal and pathological states.
