The ALS Association

ALS Ice Bucket Challenge Progress

Research Indicates TDP-43 and FUS/TLS Work Together

September 2, 2011

Although several new genes have now been linked to ALS including the recent exciting finding of mutations in the gene Ubiquilin-2 linked to familial ALS, exactly how these mutations cause disease remains unclear and is the focus of research in labs world-wide. Two proteins with similar structure and function, TDP43 and FUS, linked to familial ALS with and without frontotemporal dementia are thought to be involved in the disease, either by causing some new toxic property or by a loss of their normal function.

To identify the potential mechanism, investigators led by Brian McCabe, Ph.D., assistant professor of pathology & cell biology in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and a member of the Center for Motor Neuron Biology and Disease at Columbia University Medical Center used the Drosophila-fly model. They demonstrated that these two proteins work in tandem to support the long-term survival of motor neurons. The findings were published in the September 1, 2011 online edition of the Journal of Clinical Investigation.

The investigators demonstrate that the drosophila TDP-43 and FUS/TLS proteins bind to each other, and using the mutant proteins linked to familial-ALS, they show that these proteins work together in a common genetic pathway. They show that FUS/TLS mutant Drosophila can be fully rescued by wild type human FUS/TLS but not familial ALS mutant versions. Finally they show that over expression of FUS/TLS can effectively rescue TDP-43 mutants. Their results argue that loss of a common molecular activity that requires TDP-43 and FUS/TLS could contribute to ALS, in contrast to current models suggesting toxic accumulation.

“The two genes make proteins with similar form and function, which suggested to us that they could work together, and that disruptions of either gene would affect neuronal survival,” said Dr. McCabe, who was awarded his first grant for ALS research from The Association. “I am very grateful to The ALS Association for my first ALS grant on ALS2, which set us off on this path,” added Dr. McCabe.

“Understanding how these two proteins cause disease is critical for therapeutic development. Further studies together with this new finding will provide the necessary clues to help intervene and develop appropriate treatments," commented ALS Association Chief Scientist Lucie Bruijn, Ph.D.

To read a related media release, visit News release from Columbia University Medical Center.

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