Mutations in the FUS gene, which are the major cause of juvenile forms of amyotrophic lateral sclerosis (ALS), are linked to the loss of motor neurons. European researchers have now found that these mutations also affect other cell types in the brain.
The French-German study, “Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis,” appeared in the journal Acta Neuropathologica.
High levels of FUS (fused in sarcoma), either the normal or mutant forms, kill motor neurons, and certain mutations change the protein’s location, which might impair the normal functioning of neurons.
To further explore the mechanisms by which mutant FUS contributes to ALS, researchers used mice carrying a genetic defect that mimics human ALS-FUS patients. These animals had progressive loss of motor neurons and molecular changes similar to those seen in ALS-FUS.
Using genetic tools, researchers were able to turn off mutant FUS in specific cell populations to observe how this protein works. Indeed, they turned off the expression of mutant FUS in motor neurons only, but left it intact in other brain cells such as oligodendrocytes. These cells support and protect motor neurons by creating a myelin layer around them to ensure that electrical signals go through a motor neuron to a muscle cell.
They observed that turning off mutant FUS in motor neurons protected these cells from death, proving that this abnormal form of FUS is key to triggering motor neuron damage and death.
However, even with no mutant FUS in the motor neurons, oligodendrocytes were abnormal and damaged, with signs of demyelination. These mice still developed muscle weakness, though later than those with intact expression of mutant FUS in the motor neurons.
Together, these results support the idea that expression of mutant FUS in motor neurons leads to cell death, but the appearance of motor symptoms is caused by the action of this abnormal protein in both motor neurons and other cell types as well, including oligodendrocytes.
“In this study we show that a … mutation in the endogenous [FUS] gene, that is similar to the most severe mutations in juvenile ALS, partially recapitulates ALS-FUS pathology and triggers mild progressive ALS-like symptoms,” researchers wrote. “We demonstrate that this [FUS] mutation is associated with motor neuron degeneration …, while [neuronal] damage and demyelination occur independent of mutant FUS expression in motor neurons.”