The ALS Association

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Loss of ALS-Related TDP-43 Protein Causes Disease in Animal Model

March 13, 2014

Researchers at the University of Massachusetts Medical School in Worcester have shown that loss of an ALS-related protein, TDP-43, causes degeneration of motor neurons, the cells affected in the disease. This ALS Association-supported study was published in the journal Proceedings of the National Academy of Sciences USA.

Aggregates of the TDP-43 protein are found in dying motor neurons in almost all ALS cases. How those aggregates contribute to the disease process is unknown. One possibility is that the accumulation of TDP-43 protein in the aggregates reduces the amount of functional protein, and that reduction contributes to the dysfunction and eventual death of motor neurons.

To test that possibility, researchers led by Association-supported scientist Zuoshang Xu, M.D., Ph.D., partially silenced the TDP-43 gene in the central nervous system in mice, primarily in support cells called astrocytes. The affected mice developed a progressive neurodegenerative disease that ultimately led to paralysis and death. Loss of TDP-43 led to changes in the levels of multiple other proteins, an effect which was also observed in part in the spinal cords of humans with ALS.

“These important results tell us that loss of TDP-43 may contribute to the disease process and amplify previous findings on the importance of astrocytes in the disease process,” said Lucie Bruijn, Ph.D., MBA, Chief Scientist for The Association. “If further experiments confirm the role of loss of TDP-43, therapies that prevent TDP-43 aggregation, or replace its lost function, could be a valuable treatment approach.”

Read the press release.

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