New ALS Gene Paves the Way for Better Understanding, New Treatments

By: Richard Robinson, Science Writer
February 28, 2008

The discovery of a new gene that causes some forms of ALS will enable the development of new model systems to understand the disease and open the way for development of new treatments. The discovery, to be published today in the journal Science, links mutations in the TDP-43 gene to cases of both familial and sporadic ALS.

The research was led by Professor Christopher Shaw, M.D., at the Department of Clinical Neuroscience, King’s College London, United Kingdom, in collaboration with Jemeen Sreedharan, MRCP and Vineeta Tripathi, Ph.D., Department of Clinical Neuroscience, King’s College London, United Kingdom, and Ian Blair, Ph.D., and Garth Nicholson, Ph.D., Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, Australia.

These investigators have been funded by The ALS Association over the past years in their efforts to identify new genes linked to ALS.

“These exciting findings open up new avenues for ALS research, enabling us to develop new models for testing therapies. This is a much-needed resource for drug discovery in ALS, which has to date focused largely on mutations in superoxide dismutase 1,” commented Lucie Bruijn, Ph.D., science director and vice president of The ALS Association.

TDP-43 (TAR DNA binding protein 43) has been previously identified as a major component of the “inclusions,” or protein clumps, found in the motor neurons of ALS patients. Motor neurons die off in ALS. Until now, however, it was unknown whether TDP-43 contributed to the disease, or was an innocent bystander. The normal function of TDP-43 is unknown.

The researchers found single base changes (mutations) in the TDP-43 gene (formally known as TARDBP) in 5 affected members of 1 family, versus none of the unaffected members. They also found mutations in 2 ALS patients with no family history of the disease (sporadic ALS). No mutations were found in 1,262 unaffected controls, or in 523 other ALS cases. In all, 3 mutations were found, all affecting one region of the protein. In the familial case, the mutation was inherited in an autosomal dominant fashion (1 mutant copy was sufficient to cause the disease).

The discovery confirms that in at least some cases of ALS, TDP-43 is playing a direct role in causing the disease.

When the researchers placed the mutant gene into chick embryos, they observed abnormalities in limb development and premature cell death, although the relation of these changes to the ALS disease process is still unclear. Further work to understand the protein’s functions will lead to clues that will aid in therapy development.

“The identification of TARDBP gene mutations in ALS places TDP-43 at center stage as a potential cause of motor neuron degeneration. Critically, these mutations will give scientists around the world a new tool to explore the disease process and hopefully accelerate drug discovery,” Dr. Shaw said.

A second study, published online by the journal Annals of Neurology, identifies TDP-43 mutations in another ALS family. TDP-43 was first found in ALS inclusions in 2006. While TDP-43 mutations appear to be a rare cause of ALS, their discovery should lead to a deeper understanding of the protein’s role in the majority of ALS cases.

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