Stem Cells AssistAmyotrophic Lateral SclerosisResearch
By Richard Mollard, MBA, PhD*

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a gradual onset disease affecting approximately 1 in 100 000 people, predominantly in adulthood. The disease attacks motor neurons, which are nerve cells in the brain and spinal cord that control muscle function. The death of these motor neurons causes a muscle weakness that becomes progressively worse resulting ultimately in paralysis and death.

In many cases, there is no known cause of the disease, but in a subset of patients with an inherited form of ALS, a mutation has been found in a gene known as SOD1. Mice that have this same mutation also develop ALS.

Earlier studies on these mice have shown that it is not just the motor neurons with the mutant SOD1 gene that are involved in causing ALS, but also the support cells that surround the motor neurons. Two papers recently published in Nature Neuroscience^1,2 suggest which support cells are involved and how.

In the body, the most common type of support cells are astrocytes. When researchers took normal motor neurons made from mouse embryonic stem cells or fetal mouse spinal cords and grew them with astrocytes that had the SOD1 mutation, the motor neurons died in a similar way as they do in ALS. How did this happen? Researchers went on to show that the mutant astrocytes released a toxin that damaged the motor neurons.

The normal SOD1 gene makes a protein that plays a crucial role in providing the energy required for cells to function. Mutations, however, can change a cell’s ability to eliminate this protein properly when it is no longer needed. It is believed that something associated with this abnormal elimination process results in the production of a toxic protein (or proteins) that destroys motor neurons.

Understanding that astrocytes are involved in the onset of disease is important in designing therapies for ALS. For example, replacing motor neurons alone would not be sufficient to treat the disease as existing astrocytes could soon damage the new neurons.

This work also illustrates how useful embryonic stem cells might be in future studies. Motor neurons made from embryonic stem cells appear to act similarly to motor neurons taken directly from the mouse. Because embryonic stem cells offer a more readily available source of cells , in the future, astrocytes and motor neurons made from embryonic stem cells carrying the SOD1 mutation may be used to test and identify new drugs that can treat some forms of ALS.

Notes
1. Di Giorgio et al., (2007). Nat Neurosci. 10(5):608-614. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model.

2. Nagai M, et al., (2007). Nat Neurosci. 10(5):615-622. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons.

*Author affiliation
Richard Mollard, MBA, PhD
Head: Stem Cells, Respiratory Development and Tissue Engineering
The Department of Biochemistry and Molecular Biology
Monash University
Clayton 3800
Australia

Posted March 18, 2008