Gauthier-Kemper et al. identify tau's membrane tether and show how the protein breaks free in a form of dementia.
Some cases of frontotemporal dementia (FTD) and Alzheimer's disease (AD) have similar symptoms and a common molecular malfunction. Microtubule (MT)-binding tau proteins that normally settle in axons bunch up in the cell body, which can kill the neuron. One difference between the diseases relates to tau phosphorylation. In AD, tau is hyperphosphorylated, which might allow the protein to abscond to the cell body by breaking its connection to MTs. But in one of the most common inherited forms of FTD, mutant tau carries fewer phosphate groups than normal. Researchers haven't explained how this hypophosphorylated form of the protein gets loose.
Tau links to the cell cortex and adjusts MT dynamics during processes such as axonal growth. Gauthier-Kemper et al. found that the extensions that sprouted from neural cells carrying a form of mutant tau from FTD patients were fragile and highly dynamic, rapidly elongating and then collapsing. In the brain, such behavior might cause synapses to disconnect. However, Gauthier-Kemper et al. showed that this version of tau can still attach to MTs, ruling out one possible explanation for its mislocalization to the cell body.
Instead, the problem appears to be tau's connection to the cell cortex. The researchers determined that the protein annexin A2 normally fastens tau to the plasma membrane. But mutant tau didn't bind annexin A2 and could thus escape from the axon tip, perhaps because the mutant's reduced phosphorylation prevents it from making the connection.
