The ALS Association

ALS Ice Bucket Challenge Progress

New Insights into ALS FUS Mutation Disease Pathways

April 5, 2017

Mutations in the FUS gene cause familial (inherited) ALS, through unknown mechanisms. Previous research on other ALS-causing genes has shown that those mutant genes harm not only motor neurons, but other types of cells in the central nervous system. That led Dr. Erik Storkebaum of the Max Planck Institute for Molecular Biomedicine in Muenster, Germany, and Drs. Luc Dupuis and Jelena Scekic-Zahirovic, of the University of Strasbourg, France, to ask whether FUS mutations also harm cells besides motor neurons.

To understand which cell types are harmed by mutant FUS, the investigators made a mouse model in which the mutant gene could be turned off within motor neurons, while it remained active in other cells. They first showed that when mutant FUS was turned on, the mice developed an ALS-like condition, with progressive weakness and degeneration of motor neurons. Next, they turned off the mutant gene only in motor neurons, leaving it on in other cells, including oligodendrocytes. These cells make the electrical insulation that motor neurons need to send signals to muscle. They found that turning the gene off in motor neurons prevented their death — an important result for understanding how FUS causes disease. However, they also found that oligodendrocytes were abnormal and that the mice developed weakness, although later than they would have with mutant FUS active in motor neurons as well.

(left to right) Dr. Clotilde Lagier-Tourenne and Dr. Luc Dupuis

These results show that, like other ALS-causing genes, mutant FUS causes problems in both motor neurons and other types of cells in the central nervous system. This indicates that therapies will be needed that can work in these other types of cells, in addition to motor neurons. Current efforts in therapy development are already keeping this important lesson in mind.

This work was supported by an ALS Association Investigator-initiated Awards to Drs. Dupuis of Inserm in Strasbourg, France and Clotilde Lagier-Tourenne of Massachusetts General Hospital in Boston.

Primary Reference:
Scekic-Zahirovic J, Oussini HE, Mersmann S, Drenner K, Wagner M, Sun Y, Allmeroth K, Dieterlé S, Sinniger J, Dirrig-Grosch S, René F, Dormann D, Haass C, Ludolph AC, Lagier-Tourenne C, Storkebaum E, Dupuis L. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis. Acta Neuropathol. 2017 Feb 28.

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