The ALS Association

Ice Bucket Challenge Progress

Gene Mutation Involved in Lou Gehrig’s Disease Disrupts Critical Neuronal Transport Process

February 5, 2014

In ALS Association-supported work published in the journal Neuron, researchers have shown that the ALS-associated protein TDP-43 is critical for transport within neurons.

Virtually all people with ALS have abnormal aggregates of protein in their dying motor neurons that contain TDP-43 protein. It is unknown how or whether these aggregates contribute to the disease. Mutations in the TDP-43 gene also cause a small number of ALS cases and how the mutation causes disease is also unknown.

To learn more about the normal function of TDP-43 and to understand the disease process better, J. Paul Taylor, Ph.D., of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues examined the movement of the protein using special dyes. The protein binds to thousands of different messenger RNA molecules (mRNAs), the “working copies” of genes used to make proteins.

These researchers found that normal TDP-43 is incorporated into so-called ribonucleoprotein granules, which are transported between the cell nucleus and the tip of the axon, the long extension connecting one neuron to another. The granules were transported in both directions—from the nucleus down the axon and back up the axon to the nucleus. But granules containing mutant TDP-43 protein were less likely to be moved away from the nucleus and more likely to be moved toward it. This change in average motion was seen in several disease models, including in neurons derived from ALS patient skin cells.

“Axonal transport is critical for the function of neurons,” said Lucie Bruijn, Ph.D., Chief Scientist for The Association, “and these results tell us that TDP-43 mutation has an important effect on that transport. How this alteration in transport contributes to disease is not yet known, but it provides essential new information we can use to better understand the consequences of the TDP-43 mutation. It also may help us understand the significance of the protein aggregates seen in virtually all people with ALS. That may lead to therapies targeted at these structures.”

Read the press release.

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