February 29, 2008

ALS Gene Mutation Provides New Lead

Nigel Cairns at Washington University School of Medicine in St. Louis, with colleagues there and at several other U.S. institutions, announced online Feb. 20 in Annals of Neurology that a mutation in the gene for the TDP-43 protein is the cause of amyotrophic lateral sclerosis (ALS) in a family of European descent with four affected members. Alan Pestronk, who directs the MDA/ALS Center at Washington University, was on the study team.

In May, Ian Mackenzie and colleagues showed that the presence of TDP-43 protein in abnormal clumps in nervous-system cells is associated with sporadic (nonfamilial) ALS but not with a familial form of ALS that’s caused by mutations in the gene for the SOD1 protein.

The finding provided the first compelling evidence that SOD1-related ALS might not be driven by the same mechanisms as nonfamilial ALS, which affects the vast majority of patients. It raised questions about the usefulness of mice with SOD1 mutations as a model for the human disease, although they have been widely used in this way.

The new finding of an ALS-causing mutation in the TDP-43 gene will allow scientists to breed mice with this gene flaw and study the process by which TDP-43 abnormalities cause disease. The resulting findings may shed light not only on TDP-43-related familial ALS but on the nonfamilial form of ALS, which affects the vast majority of patients.