Nature Medicine | Spoonful of Medicine

Pumping iron: Tau’s role in neuron death revealed

The protein tau has long been at the center of a debate about the causes of Alzheimer’s disease, but how the protein works is still mostly a mystery. A paper published online yesterday in Nature Medicine examines tau’s less-controversial role in Parkinson’s disease and demonstrates that the protein’s function in the brain is intimately related to the transport of iron, a big step toward understanding the molecular underpinnings of both neurodegenerative diseases.

To tease apart the function of tau, the team, led by neurobiologist Ashley Bush of the University of Melbourne, first examined autopsy tissue from people with Parkinson’s. They found iron had built up in the substantia nigra, the part of the brain that stops working in Parkinson’s disease. The team next examined tau’s relationship with iron in a mouse that lacks the protein. Tau knock-out mice older than six months showed accumulations of iron in their brains and developed the cognitive and physical impairments of Parkinson’s disease.

By giving the mice a drug that removes iron, the researchers found that they could prevent these changes. The findings suggest that tau deficiency may cause toxic iron accumulation that leads to the neurodegeneration seen in Parkinson’s disease and Alzheimer’s. The results also suggest possible therapeutic targets for neurodegenerative disease, such as such as tau replacement or iron removal, although the authors say it is still unknown whether brain damage from iron accumulation could be reversed by such therapies.

Hyoung-gon Lee, a neurobiologist who studies Alzheimer’s disease at Case Western Reserve University in Cleveland, Ohio, says the findings about tau’s role in iron export “definitely provide a new direction for how we should look at tau abnormality in neurodegenerative disease.”

In addition to teasing apart a function of tau, Bush says his team’s work also gives important insight into how mouse models are used to study Parkinson’s disease. “After seven months, the mouse model of Parkinson’s was much more complete and complex,” he says, suggesting that for age-dependent conditions such as Alzheimer’s and Parkinson’s, keeping mice into old age may make the mouse model more accurate and useful.

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