It’s sweet, it’s safe, and it looks like it could save neurons. What is it? Trehalose.

Trehalose is a natural sugar.

This natural sugar is used in the food industry as a preservative and flavor enhancer (it’s in Taco Bell’s meat filling). And curiously, medical researchers keep running into trehalose when they’re looking for ways to fight neurodegenerative diseases.

A recent example from Emory’s Department of Pharmacology: Chris Holler, Thomas Kukar and colleagues were looking for drugs that might boost human cells’ production of progranulin (PGRN), a growth factor that keeps neurons healthy. Mutations in the progranulin gene are a common cause of frontotemporal dementia.

The Emory scientists discovered two leads: a class of compounds called mTOR inhibitors — the transplant drug rapamycin is one — and trehalose. The team decided to concentrate on trehalose because it increased PGRN levels in neuronal and non-neuronal cell types, unlike the mTOR inhibitors. Their results were published at the end of June in Molecular Neurodegeneration.

The team confirmed their findings by examining the effects of trehalose on cells derived from patients with progranulin mutations. This paper is the first to include results from Emory’s Laboratory of Translational Cell Biology, which was established in 2012 to facilitate this type of “disease in a dish” approach. Cell biologists Charles Easley, Wilfried Rossoll and Gary Bassell from the LTCB, and neurologists Chad Hales and William Hu from the Center for Neurodegenerative Disease are co-authors.

The scientists converted skin cells from patients with progranulin mutations into iPS cells, and then into neuronal cells. Exposing these cells to trehalose restored their levels of progranulin production back to close to normal levels. Giving trehalose orally to mice with one disabled progranulin gene also increased progranulin levels. The authors say that future studies will focus on whether trehalose can reverse pathological or behavioral defects in these mice.

Although it was possible to see positive effects in mice with oral administration of trehalose, a large amount was necessary: the drinking water contained 2 percent of the sugar by weight. Trehalose is considered “generally recognized as safe” by the FDA, but similarly large amounts in the human diet could produce diarrhea or bloating.

This paper focused on models of frontotemporal dementia, but there is accumulating evidence that trehalose may be helpful with other conditions.

“There is the definite possibility that trehalose is good for your brain regardless of PGRN mutation status,” Kukar says. “Trehalose has many reported beneficial properties besides increasing PGRN, which is one reason we pursued it. That being said, no one has done clinical trials with trehalose examining cognition.”

A decade ago, trehalose came to the attention of Japanese scientists studying a mouse model of Huntington’s disease. More recently, trehalose was identified as a potential tool against nonalcoholic fatty liver disease. Trehalose has been tested in clinical trials for reversal of arterial aging, oculopharyngeal muscular dystrophy, and spinocerebellar ataxia.

In some of these clinical trials, trehalose is administered intravenously, even though it is possible to see effects via oral administration in large quantities.

“We aren’t sure how much trehalose gets across the blood brain barrier, but it is likely low especially when given orally,” Kukar says. “IV delivery could be challenging to administer as a drug long term.”

He says his lab is looking for trehalose derivatives and other PGRN-boosting compounds that may be more potent, as well as studying how trehalose leads to increased PGRN levels.

Other scientists have found that trehalose appears to exert its effects partly by stimulating autophagy, a cellular response to starvation or stress that involves breaking down cell components. In contrast, other sugars such as glucose and fructose shut down autophagy. Trehalose also seems to help sensitive proteins fold correctly.

“We think the effects of trehalose on autophagy and on raising PGRN are independent,” Holler says. “Trehalose does induce autophagy, but that is not a requirement for it increasing PGRN. Trehalose may have multiple beneficial effects (ie. activating autophagy and increasing PGRN) that are independent of one another.”