Mutated protein chokes off and kills neurons leading to ALS

In 2014 there was a massive undertaking to raise money to fund research for a cure to Amyotrophic Lateral Sclerosis (ALS). This fund raising effort was hugely successful raising over $100 million for ALS research across the world. ALS is a progressive degenerative disorder that affects the neurons that control the movement of your muscles. This loss of control eventually results in difficulty speaking, swallowing, and breathing. The life expectancy of most individuals with ALS is 3-4 years, although there are individuals who can live with the disorder for 10 or more years. While there is currently no known cure or treatment for ALS, researchers are working hard to discover possible causes of the disease and therefore potential treatment options. One such research group, based in Ohio, has recently published a paper explaining the role one a protein plays in starving neurons of energy and eventually killing them.

The protein in questions, called TAR DNA-binding protein 43 (or TDP-43) is important protein used by our cells to turn down the expression of certain genes. It acts as a sort of dimmer switch for a light bulb, too much light and you decrease the brightness of it. In this case, if there is too much of a gene present in the cell, TDP-43 decreases the amount present and brings it under control. Under normal conditions, this protein is located only in the nucleus of the cell however, mutations in TDP-43 can cause this protein to move to other locations within the cell. While it is known that these mutations are present in people with ALS, the mechanism by which the mutated protein contributes to ALS has previously been unknown. What these researchers found was that TDP-43 was accumulating in the mitochondria of the cell. The mitochondria are the power houses of the cell, responsible for all the energy necessary. When the protein began accumulating in the mitochondria, it started to turn down the expression of genes important in make energy. With fewer genes, the mitochondria had a harder time making the proteins necessary for producing energy. With less energy available, the neurons began to starve. As more and more TDP-43 accumulated in the mitochondria, the starvation became so severe that the neurons died. This could result in loss of muscle control and other symptoms associated with ALS.

Perhaps most interestingly, by stopping TDP-43 from entering the nucleus, the researchers were able to stop the mitochondria from failing, prevent the death of the neurons, and improve the symptoms of mice given experimental ALS. This exciting result means that a treatment for this awful disease could be in the works. There is still lots of work that needs to be done to design a drug to prevent the protein from getting into the nucleus but now we have a starting point. Along with some of the other important research to come from the ice bucket challenge there is an excitement that an effective treatment for ALS is a possibility.


Image Credit: By Frank Gaillard –, CC BY-SA 3.0,


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