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.