New ALS Mouse

Mice carrying a mutation in the gene for the TDP43 protein that's known to cause amyotrophic lateral sclerosis (ALS) in humans have been developed by MDA-supported scientists at Washington University School of Medicine in St. Louis. The mice may provide an important new research tool in this deadly disease.

Iga Wegorzewska and colleagues will publish their findings online the week of Oct. 12, 2009, in Proceedings of the National Academy of Sciences. MDA grantee Robert Baloh coordinated the research team.

Until now, most ALS research not conducted in humans has utilized mice with various mutations in the SOD1 protein, which also can cause human ALS. However, because mutations in any particular gene only cause a small percentage of human ALS cases, the availability of a new "mouse model" of the disease is expected to broaden scientists' ability to observe disease progression and the effects of experimental treatments.

About ALS

ALS is a disease in which the motor neurons, muscle-controlling nerve cells in the brain and spinal cord, are lost, causing progressive paralysis of all voluntary muscles, including those used for breathing and swallowing.

ALS usually begins in late middle age, although it can affect young people and older adults. The disease is "sporadic," meaning that it appears without any known family history, about 90 percent of the time. The disease is "familial," or is preceded by a family history, about 10 percent of the time.

Brown mouse
The mainstay of ALS research since the mid-1990s has been the “SOD1 mouse,” which was bred to have a disease-causing mutation in the SOD1 gene, the cause of a small percentage of human ALS cases. However, some investigators have questioned the extent to which these mice replicate the vast majority of cases of human ALS cases. The new “TDP43 mouse,” bred to have a mutation in a different ALS-connected gene, may provide new clues about the disease.

Various mutations in the SOD1 gene on chromosome 21 are responsible for some 1 percent to 3 percent of ALS cases. Mutations in several other genes, including the TDP43 gene on chromosome 1, have been found to cause ALS in a small number of individuals.

The cause of the vast majority of ALS cases is unknown, making it difficult to replicate the disease in laboratory animals.
 
About TDP43 and ALS

Mutations in the TDP43 gene have been found to result in ALS in families in the United States, Canada, England, Japan and France, and in a small number of people with ALS with no family history of the disease.

The TDP43 protein plays a role in the processing of RNA, which is made from DNA and carries the genetic instructions for each protein molecule made by a cell. Therefore, abnormalities in TDP43 have the potential to result in errors in the production of many different cellular proteins.

In addition, abnormal accumulations of the TDP43 protein have been noted in nerve cells in people with sporadic ALS and familial ALS who do not have TDP43 mutations (although not in cases where SOD1 gene mutations are present). Therefore, scientists have speculated that the TDP43 protein may play a role in disease causation beyond the one it plays in patients who have mutations in the TDP43 gene. (See What's going on with TDP43?)

TDP43-containing clusters also are seen in brain cells in people with frontotemporal lobe degeneration, a disorder that causes cognitive abnormalities and sometimes accompanies ALS.

About the new findings

The mice carrying the TDP43 gene mutation developed a disease resembling human ALS. They appeared normal up to about 3 months of age, after which they developed a gait abnormality. By about 4.5 months, the mice with the TDP43 mutation began losing weight and developed a "swimming" type of locomotion, dragging their bellies on the ground and using their limbs to propel them. Their average survival time was 154 days, or about five months. Normally, mice live about two years.

The brains of the mice with the TDP43 mutation showed abnormal clusters containing a protein called ubiquitin, a "tag" attached to cellular proteins targeted for destruction.  Similar clusters of ubiquitin-containing proteins are common in human cases of sporadic and familial ALS.

In the mice, the ubiquitin-containing clusters were particularly prominent in the motor cortex, the area of the brain known to be affected in ALS patients, although clusters also were seen in certain other brain regions.

The spinal cords of the mice with the TDP43 mutation had fewer nerve fibers than normal and revealed many degenerating fibers. End-stage TDP43 mutant mice showed a 20 percent loss of spinal motor neurons.

Motor neurons in the spinal cord, like those in the motor cortex of the brain, also had clusters containing the ubiquitin "destruction tag."

Interestingly, however, and in contrast to what has been observed in people with ALS, the brains and spinal cords of the mice did not contain accumulations of TDP43 itself.

The researchers say their findings suggest that the abnormal TDP43 protein produced from the mutant TDP43 gene may be toxic through alteration of protein-destruction pathways. It may cause degeneration of nerve cells and accumulations of proteins tagged for destruction in these cells.

Meaning for people with ALS

The TDP43 mutant mouse model will need to undergo further analysis to examine the ways in which it does or does not resemble various types of human ALS.

In the best-case scenario, the TDP43 mutant mouse will be found to resemble a wide range of human ALS cases, including those due to TDP43 mutations (which are rare) and at least some that aren't due to TDP43 mutations. That would make the new mouse an extremely valuable research tool in which to try new treatments before they're tested in humans.

Even if the relevance of the new mouse is confined to patients with TDP43 gene mutations, investigations in mice of precisely how mutations in this gene produce ALS-like symptoms will give scientists an additional ALS pathway to explore.

New mouse models of ALS are badly needed, as researchers are uncertain about the extent to which the commonly used SOD1 mutant mouse model resembles non-SOD1 human ALS.

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