Key to fighting brain disease could lie in boosting appetite of cells

Cells in the body are continually mopping up cellular debris. This natural process - known as "autophagy" or self-eating - stops useless material clogging up and interfering with cells' normal functions. Now a new study suggests boosting this "appetite" in brain cells could be a way to fight diseases that arise when abnormal proteins clog up the cells, such as Lou Gehrig's disease and some forms of dementia.

Sami Barmada, an assistant professor of neurology at the University of Michigan (U-M) Medical School in Ann Arbor, and colleagues, write about their findings in the journal Nature Chemical Biology.

Autophagy - based on two Greek words for "self" and "eating" - is currently a hot topic in medical research. Scientists are starting to see it as a vital function in healthy cells. It is an essential cell-maintenance task where the cell bundles up any unwanted cell debris, breaks it down, and pushes out the waste products for elimination or recycling.

Boosting natural autophagy might be better than getting drugs to do the digesting
The researchers say it is possible to use drugs to prolong the life of brain cells by increasing the digestion of certain faulty proteins that would otherwise clog them up and stop them working. But, they propose that a better way might be to boost the cells' innate autophagy and get them to clear away the clogs themselves.

In their study, they showed how some brain cells' autophagy capacity is much diminished if they become overwhelmed with an abnormal protein called TDP43.

They then showed their idea working with drugs that boosted cell autophagy in human neurons grown from stem cells and in animals. They also demonstrated a new microscope technique that allowed them to see inside the cells and observe them going about their boosted clean-up operation, as Prof. Barmada explains:

"Using this new visualization technique, we could truly see how the protein was being cleared, and, therefore, which compounds could enhance the pace of clearance and shorten the half-life of TDP43 inside cells. This allowed us to see that increased autophagy was directly related to improved cell survival."

The study also showed that different individual neurons varied in their ability to clear TDP43 and were "exquisitely sensitive to TDP43 levels," notes the team.

Lou Gehrig's disease (amyotrophic lateral sclerosis or ALS) and certain types of dementia known as frontotemporal dementia have a common feature: brain cells full of TDP43. It seems that what patients with these diseases need are brain cells that can clear this protein away, but only further research will prove this.

One of the drugs the team used to boost autophagy is an antipsychotic drug developed in the 1960s to treat people with schizophrenia. The drug has already shown some anti-dementia potential in human ALS patients, but it also has side effects.
Some of the team members are already looking for alternative compounds that could boost autophagy with fewer side effects.

Meanwhile some small studies have also suggested that people with schizophrenia who take antipsychotic drugs are less likely to develop ALS.

Prof. Barmada says he and his team are very encouraged by their findings, and the success of the new microscope technique. His new lab at U-M is already refining it so as to get a better view of what is happening inside neurons.

They are also taking a closer look at autophagy in different kinds of brain cell. For instance, by looking upstream in the protein-producing process, such as when they are encoded by genes, they may find more clues as to why disease develops and how to tackle it, he adds.

Meanwhile in January 2014, Medical News Today learned how researchers from Tel Aviv University in Israel found brain cells' lack of autophagy may be a cause of schizophrenia, and suggested the discovery may lead to new treatments for the disorder.

Written by Catharine Paddock PhD