Changes in Lipid Levels and Metabolism in Spinal Cord Mirror ALS Progression, Early Study Suggests

Changes in Lipid Levels and Metabolism in Spinal Cord Mirror ALS Progression, Early Study Suggests
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Amyotrophic lateral sclerosis (ALS) progression is associated with higher levels of specific lipids in the spinal cord and changes in their metabolism, a study in a rat model of the disease reports.

These findings may represent a defense mechanism against oxidative damage, as well as a potential treatment route for ALS patients, the scientists said.

Their research, “Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis,” appeared in the journal Scientific Reports.

Rising levels of lipids (fat molecules) as well as their altered metabolism (chemical reactions in the processing of lipids for cellular energy and health) have been seen in the spinal cord of mice with ALS-like symptoms. Similarly, data from people with this disease show higher amounts of specific lipids — ceramides, glucosylceramides and phosphatidylcholine — in the cerebrospinal fluid, the liquid surrounding the brain and spinal cord.

A team from Universidade de São Paulo, Brazil, aimed to better understand the association of changes in lipid metabolism and disease progression by analyzing the brain’s motor cortex (the region of the cerebral cortex involved in voluntary movement) and the spinal cord of an asymptomatic and symptomatic rat model of ALS.

The specific disease model used in the study mimics familial ALS, with a mutation (G93A) in the SOD1 gene leading to protein aggregation, oxidative damage, and altered function of mitochondria — the cell’s power plants.

Through a technique called mass spectrometry, the large-scale analyzes found that levels of sphingolipids — components of myelin, the fatty protective layer of nerve fibers, and of red blood cells – increased with age rather than with disease progression in the motor cortex.

But in the spinal cord, rats exhibiting ALS symptoms showed marked alterations compared to those animals still asymptomatic, including higher levels of ceramides — which help the skin retain moisture. Analysis showed a six-fold increase in several cholesteryl esters composed of polyunsaturated fatty acids (PUFAs), and lower levels of 10 cardiolipins, which are components of mitochondrial membranes.

Of note, since the observed PUFAs — such as arachidonic, eicosapentaenoic and adrenic acids — cannot be synthesized by mammals, the scientists hypothesize that their accumulation in lipid droplets in this rat model reflects a protective mechanism against oxidative stress.

Upon symptom onset, data further showed changes in ceramide metabolism — such as an increase in very long chain molecules — in the spinal cord.

Based on research indicating that astrocytes of a similar ALS rat model accumulate lipid droplets, among other alterations, the investigators then found severe astrogliosis — increased astrocyte reactivity in response to injury, and a hallmark of ALS — in the grey matter of the spinal cord ventral horn, which contains the cell bodies of specialized nerve cells (motor neurons) that control muscle contraction.

Overall, as suggested in Alzheimer’s, “cellular processes involving cholesteryl esters metabolism and transport may represent potential targets for treatment of neurodegenerative diseases,” the investigators wrote.

“The precise analysis of molecular species of lipids as performed in our study may help to further explore the role of oxidative stress regulating lipid metabolism in neurodegenerative diseases and aging,” they added.

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