Rare Daily Staff

An international team of researchers led by scientists at the National Institutes of Health and the Uniformed Services University discovered a new and unique form of amyotrophic lateral sclerosis, a rare neurodegenerative condition also known as Lou Gehrig’s disease.

Unlike most cases of amyotrophic lateral sclerosis (ALS), the disease began attacking these patients during childhood, worsened more slowly than usual, and was linked to a gene that is part of the body’s fat production system. Preliminary results suggested that genetically silencing the gene, known as SPTLC1, would be an effective strategy for combating this type of ALS.

“ALS is a paralyzing and often fatal disease that usually affects middle-aged people. We found that a genetic form of the disease can also threaten children,” said Carsten Bönnemann, senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke and a senior author of the study published in Nature Medicine. “Our results show for the first time that ALS can be caused by changes in the way the body metabolizes lipids.”

In this study, the team discovered that 11 undiagnosed patients had ALS that was linked to variations in the DNA sequence of SPLTC1, a gene responsible for manufacturing a diverse class of fats called sphingolipids.

The team worked with scientists in labs led by Teresa Dunn, professor and chair at USU, and Thorsten Hornemann, at the University of Zurich in Switzerland. Together they not only found clues as to how variations in the SPLTC1 gene lead to ALS but also developed a strategy for counteracting these problems.

Most patients are diagnosed with ALS around 50 to 60 years of age. The disease then worsens so rapidly that patients typically die within three to five years of diagnosis. In contrast, initial symptoms, like toe walking and spasticity, appeared in these patients around four years of age. Moreover, by the end of the study, the patients had lived anywhere from five to 20 years longer.

Mutations in SPLTC1 are also known to cause a different neurological disorder called hereditary sensory and autonomic neuropathy type 1 (HSAN1). The SPLTC1 protein is a subunit of an enzyme, called SPT, which catalyzes the first of several reactions needed to make sphingolipids. HSAN1 mutations cause the enzyme to produce atypical and harmful versions of sphingolipids.

At first, the team thought the ALS-causing mutations they discovered may produce similar problems. However, blood tests from the patients showed no signs of the harmful sphingolipids.

For decades Dunn’s team had studied the role of sphingolipids in health and disease. With the help of the Dunn team, the researchers reexamined blood samples from the ALS patients and discovered that the levels of typical sphingolipids were abnormally high. This suggested that the ALS mutations enhanced SPT activity.

Similar results were seen when the researchers programmed neurons grown in petri dishes to carry the ALS-causing mutations in SPLTC1. The mutant carrying neurons produced higher levels of typical sphingolipids than control cells. This difference was enhanced when the neurons were fed the amino acid serine, a key ingredient in the SPT reaction.

Previous studies have suggested that serine supplementation may be an effective treatment for HSAN1. Based on their results, the authors of this study recommended avoiding serine supplementation when treating the ALS patients. Dunn’s team performed a series of experiments which showed that the ALS-causing mutations prevent another protein called ORMDL from inhibiting SPT activity.

“Our results suggest that these ALS patients are essentially living without a brake on SPT activity. SPT is controlled by a feedback loop. When sphingolipid levels are high then ORMDL proteins bind to and slow down SPT. The mutations these patients carry essentially short circuit this feedback loop,” said. Dunn. “We thought that restoring this brake may be a good strategy for treating this type of ALS.”

To test this idea, the Bönnemann team created small interfering strands of RNA designed to turn off the mutant SPLTC1 genes found in the patients. Experiments on the patients’ skin cells showed that these RNA strands both reduced the levels of SPLTC1 gene activity and restored sphingosine levels to normal.

“These preliminary results suggest that we may be able to use a precision gene silencing strategy to treat patients with this type of ALS. In addition, we are also exploring other ways to step on the brake that slows SPT activity,” said Bonnemann. “Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.”

Photo: Carsten Bönnemann, senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke

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