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Oct 31
2018

Most common ALS-linked gene helps regulate lipid metabolism

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A new study by Packard scientist Jiou Wang reveals that C9orf72 helps to regulate how cells use fats for energy when starved of glucose.

Although researchers linked a mutation in a gene called C9orf72to ALS and frontotemporal dementia (FTD) seven years ago, the actual function of the gene has remained a mystery. Now, a new study in Genes and Development led by Packard scientist Jiou Wang reveals that C9orf72 helps to regulate how cells use fats for energy when starved of glucose. The ALS/FTD-linked mutation disrupts this process, which stresses cells and potentially contributes to disease. 

ALS and FTD are neurodegenerative disorders that primarily affect motor and cortical neurons, respectively. Aside from the neurodegeneration, many individuals with ALS also develop an unusually high metabolic rate, a feature of the illness that has confused scientists for decades. Scientists developed a variety of hypotheses but never zeroed in on the exact metabolic defects in ALS.

At the same time, scientists have shown that mutations in C9orf72can cause the most common forms of neurodegeneration in ALS and FTD. However, there is still a lack of understanding of the job of normal C9orf72in the cell, or the disease-causing contributions from inadequate amounts of the C9orf72 protein, which occurs when an individual inherits one mutant copy of C9orf72and one normal copy. 

Wang and colleagues deleted both copies of C9orf72in mouse embryonic fibroblasts to see what went wrong in the cell, which would give them clues about the normal job of the C9orf72 protein. Compared to control cells, the C9 knockout cells had abnormal changes in the amounts of proteins involved in lipid metabolism, a difference that was enhanced when the cells were starved of glucose. These cells also had more lipid droplets, small organelles in which the cell stored extra fatty acids.

When the researchers tracked the lipid droplets over time, they found that the mouse cells lacking C9orf72also showed an increased turnover in fatty acids, indicating an increase in lipid metabolism. The change wasn’t benign—the cells also showed markers of higher oxidative stress, especially when starved of glucose. Further experiments revealed that a protein called CARM1, which regulates the cellular disposal and recycling pathway known as autophagy by altering the expression of various genes, interacts with C9orf72. Mouse cells lacking C9orf72had higher levels of CARM1 protein, and CARM1 levels increased further with glucose starvation. The degradation of CARM1 in the lysosome requires the presence of C9orf72. With no functional C9orf72 genes, CARM1 levels increased. Deleting both C9orf72and CARM1from mouse embryonic fibroblasts reversed the high levels of lipids, lipid droplets, and free fatty acids seen in the C9orf72 knockout cells. 

These cell and mouse studies provided strong hints that C9orf72played a role in the abnormal metabolism seen in ALS patients, but Wang needed to see the effects in humans with disease. When the team examined ALS patient cells and tissues, including lymphocytes, stem cell-derived motor neurons, and spinal cord tissues, carrying the C9orf72mutation, they found the cells had higher CARM1 levels than controls, abnormal lipid droplet or fatty acid levels, as well as increased markers of oxidative stress. Taken together, the authors conclude, the results show that mutations in C9orf72disrupt normal lipid metabolism in ALS.

This study, then, helps to solve two major ALS-related mysteries: a function of the unmutated C9orf72gene and a potential cause of the metabolic issues seen in the disease.

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