TAU MEDIATES DEGENERATION THROUGH INTERACTION WITH ACTIN
Tau is a microtubule binding protein that is believed to be important for the assembly and stabilization of microtubules. Six tau isoforms are expressed in adult human brain, produced from a single gene on chromosome 17q21 by alternative mRNA splicing. In nerve cells tau is normally found in axons, but in neurodegenerative diseases called tauopathies it is redistributed to the cell body and dendrites.
Tau is a phosphoprotein, and phosphorylation negatively regulates the ability of tau to interact with microtubules. The accumulation of hyperphosphorilated tau is associated with Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration and frontotemporal dementia including its variant known as Pick’s disease. Many evidences support the suspect that pathologic tau contributes to the pathogenesis of such conditions, although molecular mechanisms have remained elusive.
In vitro researches have found interactions between tau and actin, and other studies suggested that actin aggregation can trigger cell death. Moreover, actin-rich inclusions have been found in the brains of patients with various neurodegenerative disorders. However it is not known whether these interactions can cause neurodegeneration in vivo.
Mel B. Feany and colleagues at Harvard Department of Pathology conducted an in vivo study in Drosophila melanogaster, which provides evidences that tau can mediate neurodegeneration through interaction with actin (Fulga T. A., et al., Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nature Cell Biol. 9, 139-148, 2007).
The study, using several fruit-fly strains that expressed wild-type human tau or a mutant form of tau associated with familial fronto-temporal dementia, demonstrates interactions between hyperphosphorylated tau, modification of the actin cytoskeleton and neurotoxicity.
Confirmation of Feany’s results in other in vivo models, and identification of pathogenic events that are downstream of this interaction, are the next two steps toward an understanding of tau pathogenic role in neurodegeneration.