10027/8577
Gerardo Morfini
Gerardo
Morfini
Nicholas Kanaan
Nicholas
Kanaan
Nichole LaPointe
Nichole
LaPointe
Gustavo Pigino
Gustavo
Pigino
Kristina R. Patterson
Kristina R.
Patterson
Yuyu Song
Yuyu
Song
Athena Andreadis
Athena
Andreadis
Pathogenic Forms of Tau Inhibit Kinesin-Dependent Axonal Transport Through
a Tau-Dependent Mechanism Involving Activation of Axonal Phosphotransferases
University of Illinois at Chicago
2012
untagged
2012-08-20 00:00:00
Journal contribution
https://indigo.uic.edu/articles/journal_contribution/Pathogenic_Forms_of_Tau_Inhibit_Kinesin-Dependent_Axonal_Transport_Through_a_Tau-Dependent_Mechanism_Involving_Activation_of_Axonal_Phosphotransferases/10779908
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.