Gene responsible for cases of Lou Gehrig's disease

Published in the current online edition of Nature Genetics, the study on 200 human subjects with ALS was led by Doctors Guy Rouleau, Edor Kabashi, Paul Valdmanis of the Research Centre of the Centre hospitalier de l'Universitй de Montrйal (CRCHUM). The team identified several genetic mutations in the TDP-43 gene by studying ALS patients from France and Quebec. They established TDP-43 as the gene responsible for up to five percent of the ALS patients.

The breakthrough is the result of teamwork with peers from the Waterloo and Laval universities in Canada and the Fйdйration des maladies du systиme nerveux and the Institute of Biology (Unitй de Neurologie Comportementale et Dйgйnйrative) in France.

Building on past studies

In 1993, Dr. Rouleau and his team also helped identify “superoxide dismutase” as the gene that causes the disease in 10 to 20 percent of all familial cases of ALS. This cornerstone study led to development of several mouse and rat models of ALS that closely resemble the motor neuron disorder observed in ALS patients. These models have been very useful to study molecular and cellular mechanisms of disease and to test treatments for ALS.

TDP-43’s normal function is to bind and splice RNA. Two years ago, a team from the University of Pennsylvania discovered TDP-43 in abnormal protein clumps, referred to as aggregates, in motor neurons of ALS patients. However, it was not certain whether TDP-43 causes motor neuron disease or is just a pathological marker.

“The identification of additional mutations in TDP-43 in other ALS patients will confirm that this gene is a prominent cause of this type of disorder,” said Dr. Rouleau, director of the Sainte-Justine Hospital Research Centre. “Animal models over-expressing the mutations identified in this study will provide crucial insight into how TDP-43 aggregate and ultimately kill motor neurons.”

“This discovery is a step towards the development of therapies for people suffering from this terrible disease and possibly other neurodegenerative diseases," said Dr. Kabashi.-University of Montreal