Disease Spread in Mouse Model Places Spotlight on Protein Misfolding in ALS

October 10, 2014

In a study supported by The ALS Association and published in the journal Acta Neuropathologica, researchers have demonstrated a potential disease mechanism for the spread of ALS pathology through the central nervous system. The finding sheds light on a likely source of disease progression and a promising target for therapy.

The ALS disease process can begin in any one of several different regions of the central nervous system. The progression of symptoms during the disease course suggests that the disease may spread from affected to unaffected cells. A possible mechanism for that spread is the transmission of misfolded proteins from one cell to an adjacent cell, causing protein misfolding there and inducing neurodegeneration as a result.

To test that model of disease spread, researchers transferred cells from rapid-progression ALS mice that expressed high levels of mutant SOD1 protein, one of the most common genetic causes of ALS. The cells were injected into the spinal cord of a different SOD1 mutant, one whose protein levels were too low to cause disease.

Researchers found that injection of the cells from the rapid-progression mouse caused the second mouse to develop disease, accompanied by a large increase in the amount of misfolded SOD1 protein. This suggests that the misfolded protein from the rapid-progression mutant induced misfolding in the second mouse, thus contributing to disease progression.

“The results of this study suggest that interrupting the misfolding or cell-to-cell spread of misfolded protein may be a therapeutically useful strategy,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The Association. “The Association is pursuing this strategy through our funding of other research groups that are developing antibodies that prevent that misfolding.”

The research was performed by 2014 Milton Safenowitz Post-doctoral Fellow Jacob Ayers, Ph.D., under the direction of David Borchelt, Ph.D., both of the University of Florida at Gainesville.

Read the press release.

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