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Kanaan NM, Morfini GA, Lapointe NE, Pigino GF, Patterson KR, Song Y, Andreadis A, Fu Y, Brady ST, Binder LI. Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci. 2011 Jul 6;31(27):9858-68. PubMed.
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Michigan State University
Some studies suggest that tau inhibits axonal transport by clogging microtubules and interfering with the kinesin motor protein responsible for anterograde transport. However, our work clearly demonstrates that this is not the case in the context of the molecular mechanism we are studying. We show that tau-mediated inhibition of anterograde transport does not require microtubule binding, the other domains of tau (e.g., microtubule binding regions or the C-terminus), or tau aggregation, although aggregation is a means by which the phosphatase activation domain (PAD) can become exposed. The PAD peptide and N-terminal isoforms (6D and 6P) are key in demonstrating this point, as they do not bind microtubules and do not aggregate, but they do illicit significant inhibition of anterograde axonal transport via the PP1-GSK-3 signaling cascade. Our results are consistent with the concept that axonal transport is regulated by the activity of phosphotransferases on the motor proteins, and that these regulatory mechanisms go awry in numerous neurodegenerative diseases.
The earliest form of tau pathology appears to be neuropil threads, which are aggregations of abnormal tau in the axons and dendrites of affected neurons. We found abnormal, PAD-exposed tau (double labeled with AT8 and TNT1 antibodies) within neuropil threads, suggesting the deleterious mechanisms identified in our studies are at work in these processes. While our work focuses on the anterograde transport in the axon of neurons, the data presented are likely applicable across most of the cellular compartments where tau pathology accumulates. As the disease progresses, the accumulation of abnormally modified and aggregated tau continues in the somatodendritic compartment of neurons where kinesin-based anterograde transport along microtubules is critical to normal function. A natural extension of our work is the prediction that kinesin-based transport along microtubules is disrupted by the accumulation of PAD-exposed tau and activation of the same signaling cascade in the cell body and dendrites of neurons.
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