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Pathogenic Forms of Tau Inhibit Kinesin-Dependent Axonal Transport Through a Tau-Dependent Mechanism Involving Activation of Axonal Phosphotransferases

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Title: Pathogenic Forms of Tau Inhibit Kinesin-Dependent Axonal Transport Through a Tau-Dependent Mechanism Involving Activation of Axonal Phosphotransferases
Author(s): Morfini, Gerardo; Kanaan, Nicholas; LaPointe, Nichole; Pigino, Gustavo; Patterson, Kristina R.; Song, Yuyu; Andreadis, Athena
Abstract: Aggregated filamentous forms of hyperphosphorylated tau (a microtubule-associated protein) represent pathological hallmarks of Alzheimer’s disease (AD) and other tauopathies. While axonal transport dysfunction is thought to represent a primary pathogenic factor in AD and other neurodegenerative diseases, the direct molecular link between pathogenic forms of tau and deficits in axonal transport remain unclear. Recently, we demonstrated that filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Here, we demonstrate that amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway in axoplasms isolated from squid giant axons. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Importantly, immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity, an early marker of pathological tau. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3 and inhibition of FAT. Results from these studies reveal a novel role for tau in modulating axonal phosphotransferases and provide a molecular basis for a toxic gain-of-function associated with pathogenic forms of tau.
Issue Date: 2011-07
Publisher: Society for Neuroscience
Citation Info: Kanaan, N. M., Morfini, G. A., LaPointe, N. E., Pigino, G. F., Patterson, K. R., Song, Y., Andreadis, A., Fu, Y., Brady, S. T., & Binder, L. I. 2011. Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. Journal of Neuroscience, 31(27): 9858-9868. DOI: 10.1523/JNEUROSCI.0560-11.2011
Type: Article
Description: © 2011 by Society for Neuroscience, Journal of Neuroscience DOI: 10.1523/JNEUROSCI.0560-11.2011
ISSN: 0270-6474
Sponsor: This work was supported by NIH T32 AG020506-07 (NMK); NIH AG09466 (LIB); NIH NS23868, NS23320, NS41170 (STB); as well as 2007/2008 MBL Summer Research Fellowships and an ALS/CVS Therapy Alliance grant (GM).
Date Available in INDIGO: 2012-08-20

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