Protein plays Jekyll and Hyde role in Lou Gehrig's disease

Brandeis study sheds light on ALS

Waltham, MA—Amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig's disease, is a fatal neurodegenerative disease caused by the death of motor neurons in the brain and spinal cord that control muscle movements from walking and swallowing to breathing. In a groundbreaking study this week in PLoS Biology, Brandeis and Harvard Medical School scientists report key findings about the cause and occurrence of the familial form of ALS.

For the past three years, Brandeis chemist Jeff Agar and his colleagues have studied the rare, familial form of ALS (fALS) as a window into the sporadic form of ALS, which accounts for 90 percent of all cases. Scientists discovered fifteen years ago that mutations in the gene that makes the protein, superoxide dismutase, are responsible for inherited ALS, but how these mutations cause ALS remain a mystery. Researchers believe deciphering the mechanisms at work in inherited ALS will clear the way to understanding and treating sporadic ALS, in large part because clinical symptoms are identical in both forms of the disease.

Agar's research demonstrated that fALS is caused by two synergistic properties of the protein superoxide dismutase, creating toxic levels of the protein in motor neurons. "We discovered that increased protein unfolding and the propensity of the proteins to aggregate, (to clump together) are the major factors in the familial form of ALS," explained Agar.

This propensity of proteins to unfold and clump together amounts to what scientists call a 'toxic gain of function.' Many diseases are caused by a loss of protein function, but some, like ALS, are linked to a gain of function in which a protein takes on a new role, unrelated to the one it is supposed to perform in healthy cells.