Most research on Lou Gehrig's disease therapeutics has been based on the assumption that its two forms (sporadic and hereditary) are similar in their underlying cause.
Now, researchers at the University of Pennsylvania School of Medicine have found an absolute biochemical distinction between these two disease variants, suggesting that current approaches to drug discovery should be re-examined.
About 5 percent of all cases of Lou Gehrig's disease, or amyothrophic lateral sclerosis (ALS), are passed from generation to generation. The most common genetic variant in this familial form is caused by a mutation in the SOD-1 gene. The researchers looked at a large set of ALS patients, including hereditary cases, both with and without the SOD-1 mutation.
The present study , published in the May issue of the Annals of Neurology , was conducted by Penn; a group led by Ian Mackenzie from the University of British Columbia; the University of Munich; and others across the U.S. and Canada.
"Most ALS research has focused on how mutant SOD-1 proteins are toxic to nerve cells," says senior author John Trojanowski, MD, PhD, who directs the Penn Institute on Aging. Last year, Penn investigators led by co-author Virginia Lee, PhD, who directs the Penn Center for Neurodegenerative Disease Research, identified TDP-43 as the major disease protein in sporadic (non-hereditary) forms of ALS, which are not those caused by SOD-1 gene mutations.
By examining the various forms of ALS in post-mortem tissue, the researchers found that TDP-43 was the disease protein in sporadic ALS cases, but not in patients with SOD-1 mutations, all of whom have the familial form of ALS. Patients with the SOD-1 mutation account for about 1 percent of all ALS cases.