Faculty Collaborative Work

Altered amino acid metabolism

Amino acids are the building blocks that make up proteins and specialized fat molecules called sphingolipids, which are abundant in the nervous system. Low levels of the amino acid serine force the body to incorporate a different amino acid in sphingolipids, which changes their structure. These atypical sphingolipids then accumulate, which may contribute to peripheral nerve damage. While the team observed this accumulation in diabetic mice, the same amino acid switch and sphingolipid changes occur in a rare human genetic disease marked by peripheral sensory neuropathy, indicating that the phenomenon is consistent across many species.

To determine whether long-term, chronic serine deficiency drives peripheral neuropathy, the researchers fed mice either control or serine-free diets in combination with either low-fat or high-fat diets for up to 12 months. The researchers were surprised to find that low serine, in combination with a high-fat diet, accelerated the onset of peripheral neuropathy in the mice. In contrast, serine supplementation in diabetic mice slowed the progression of peripheral neuropathy, and the mice fared better.  

The researchers also tested the compound myriocin, which inhibits the enzyme that switches out serine for another amino acid as sphingolipids are assembled. Myriocin treatment reduced peripheral neuropathy symptoms in mice fed a high-fat, serine-free diet. These findings underscore the importance of amino acid metabolism and sphingolipid production in the maintenance of a healthy peripheral nervous system. 

Serine deficiency has also been associated with various neurodegenerative disorders. For example, the team previously found a link between altered serine and sphingolipid metabolism in patients with macular telangiectasia type 2, a condition that causes vision loss. In mice, reduced serine led to increased levels of atypical retinal sphingolipids and reduced vision. Serine is currently being tested in clinical trials for its safety and efficacy in treating macular telangiectasia and Alzheimer’s disease.

Peripheral neuropathy is typically managed with dietary changes to reduce blood sugar levels, as well as pain relievers, physical therapy, and mobility aids, such as canes and wheelchairs. Foods naturally rich in serine include soybeans, nuts, eggs, chickpeas, lentils, meat, and fish, and serine supplements are inexpensive and available over the counter. 

Yet the researchers say it’s premature to advise people with diabetes to take serine supplements to prevent neuropathy.

“You would likely need to take a lot to make a difference, and not everyone needs extra serine,” Metallo says. “We need more time to understand serine physiology in humans and explore potential downsides to supplementation.”

To this end, Metallo and Handzlik are now developing a serine tolerance test, similar to a glucose tolerance test used to diagnose diabetes.

“We want to identify those at highest risk for peripheral neuropathy so we can treat only those who might benefit most,” says Handzlik.