July 13, 2021

Changes in metabolism may produce neurofibromatosis traits, study finds Research in fruit flies reveals how nerve cell changes disrupt normal metabolic rate.

July 13, 2021

JUPITER, FL Neurofibromatosis type 1, a disease that features nerve tumors, an elevated risk of autism, and many other symptoms, has long been tied to mutations in a gene called NF1. Scientists at Scripps Research have discovered important clues about how that gene disruption may lead to disease.

The scientists' findings appear July 13 in the journal Nature Communications. The team led by Seth Tomchik, PhD, an associate professor of neuroscience at Scripps Research, found that in a standard model organism, the Drosophila melanogaster fruit fly, mutating the fly version of NF1 alters the function of a specific population of nerve cells. This in turn leads to widespread metabolic disruptions, including a markedly higher metabolic rate essentially a faster consumption of energy in these insects.

The findings dovetail with prior hints of metabolic abnormalities in neurofibromatosis type 1 patients, and suggest the possibility that these abnormalities are key features and drivers of the neurofibromatosis disease process.

Our findings suggest that we should look at the neuronal regulation of metabolism in people to better understand this disease, and potentially find more effective ways to treat it, Tomchik says.

Neurofibromatosis type 1 arises when just a single copy of NF1, of the two normally found in cells, is mutated and inactivated. The disorder occurs in one out of every 3,500 or so live births, and currently about 100,000 people in the United States are living with it. Benign tumors that grow from nerves anywhere in the body are one of the classic features of neurofibromatosis type 1, but the disorder can include epilepsy, learning disabilities, vision problems, and skin lesions, along with a higher risk of autism spectrum disorder, cancers, and heart disease.

The protein encoded by the NF1 gene, neurofibromin, normally works, among other things, to regulate the activity of a multifunctional, growth-related protein called Ras. Its disruption leads to more Ras activity. Ras is also hyperactive in many cancers. However, scientists don't know much more than that about the disease process. The only specific treatment, a drug called selumetinib that was approved by the Food and Drug Administration in 2020, can shrink or prevent the growth of a type of benign nerve tumor, but it is applicable only to a subset of children with the disease, and is not a cure.

Graduate student Valentina Botero is first author on a study of how NF1 mutations disrupt metabolism in fruit flies.

LINK:	https://www.scripps.edu/news-and-events/press-room/2021/20210731-tomch...
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