Fat molecules may limit damage to nerve cells in ALS, study finds
Certain fats could have benefits, researchers say
Fat molecules called polyunsaturated fatty acids, or PUFAs, can help lessen nerve damage in amyotrophic lateral sclerosis (ALS), according to a study of fruit flies and cell models.
Previous studies have shown that consumption of omega-3 fatty acid, a type of PUFA, is associated with a lower risk of developing ALS as well as slower ALS progression in people with the disease. The study’s results offer a potential explanation for those associations.
“From our findings we can conclude that enhancing levels of omega-3 fatty acids in the brain may be beneficial in [ALS],” Adrian Isaacs, PhD, co-author of the study and a professor at University College London, said in a university news story. The next step for scientists, Isaacs said, is to determine which fatty acid to test in humans and how to deliver it in sufficient quantities to the brain. “Then, we want to take these findings forward into a clinical trial,” he said.
The study, “Neuronal polyunsaturated fatty acids are protective in ALS/FTD,” was published in Nature Neuroscience.
ALS is caused by the death and dysfunction of motor neurons, the specialized nerve cells that are responsible for controlling movement. Some ALS cases are associated with genetic mutations, but the underlying molecular mechanisms that drive motor neuron damage in ALS aren’t fully understood.
Fat molecules and cell health
The study began with an analysis of gene activity in fruit flies, which are commonly used as an animal model to study neurological diseases. The researchers worked with fruit flies carrying a mutation in the C9ORF72 gene, the most common genetic cause of ALS.
The scientists noticed that nerve cells in flies carrying this disease-causing mutation showed notable reductions in the activity of many genes involved in the metabolism of fat molecules. These genes were also altered in cells collected from the spinal cords of ALS patients.
Further molecular analyses looking at the specific types of fat molecules in the flies revealed an abnormality in the kinds of phospholipids, a type of molecule that makes up the membrane of a cell, that were present.
Phospholipids are long molecules made up of a head region connected to two tails of fatty acids, long chains of carbon atoms that are covered with hydrogen atoms. In some phospholipids, tail regions are entirely covered with hydrogen atoms. These are called saturated fatty acids. Unsaturated fatty acids have tail regions with fewer hydrogen atoms. Fatty acids with more than one site of reduced hydrogen covering are called polyunsaturated, or PUFAs.
The researchers found that ALS flies showed substantially reduced PUFA levels and relatively higher amounts of saturated phospholipids.
Analyses using human nerve cells revealed similar changes in phospholipid makeup. And similar results were found when the researchers analyzed brain samples from people with frontotemporal dementia, a form of dementia that often affects people with ALS.
The researchers speculated that increasing the amount of PUFAs in the brain might be beneficial in ALS. To test the idea, they tried feeding ALS flies more PUFAs. This slightly increased the flies’ lifespans, by 12% to 15%. In contrast, feeding the flies with saturated fatty acids or fatty acids lacking only one hydrogen either had no effect or reduced survival.
The scientists then tried engineering the flies so that their nerve cells would express high levels of proteins that can perform lipid unsaturation, turning saturated fatty acids into PUFAs. This had a more dramatic effect, increasing survival by a median of 67%. In human nerve cells, increasing the generation of PUFAs likewise reduced the toxic effects of ALS-causing mutations.
“This suggests a functional role for lipid unsaturation in modifying neurodegeneration in ALS,” the scientists wrote.
Engineering ALS flies so that their nerves had reduced ability to make PUFAs consistently reduced survival. In flies that didn’t have ALS, however, reducing levels of PUFA-making proteins in nerve cells did not affect survival. These data suggest that low PUFA levels don’t cause outright damage to nerve cells, but may make motor neurons more vulnerable to damage that drives ALS.
“Overall, the results presented in the present study identify dysregulated lipid metabolism as a direct contributor to neuronal toxicity in [ALS caused by C9ORF72 mutations] and suggest that modulating neuronal lipid saturation is a promising approach for ameliorating neurodegeneration,” the researchers concluded.
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