Mutation Causes Death of Motor Neurons in ALS

The progressive degeneration of motor neurons in ALS eventually leads to their death. Lack of motor neurons causes the brain to lose the ability to initiate and control muscle movement, leading to progressive paralysis. On the molecular level, the disorder is characterized by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. TDP-43 had been previously identified as a major component of the protein inclusions found in ALS patients' motor neurons.

Investigators at King's College (London, UK) compared gene maps of ALS patients with those of a large number of normal individuals. They reported in the February 28, 2008, online edition of the journal Science that there were single base mutations in the TDP-43 gene in five affected members of one family, compared to none in unaffected members. They also found mutations in two 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, three mutations were found, all affecting one region of the protein. In the familial case, the mutation was inherited in an autosomal dominant fashion (one mutant copy was sufficient to cause the disease).

In a second report published in the February 20, 2008, online edition of the Annals of Neurology the investigators presented additional evidence of a direct link between altered TDP-43 function and neurodegeneration.

"The identification of TDP-43 gene mutations in ALS places TDP-43 protein 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,” said senior author Dr. Christopher Shaw, professor of clinical neuroscience at King's College.


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