Mutated Gene Causes Nerve Cell Death

The British astrophysicist Stephen Hawking is likely to be the world's most famous person living with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. ALS is a progressive disease affecting motor neurons, nerve cells that control muscle function, and nearly always leads to death. Researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna have now identified a completely new mechanism in the onset of motor neuron diseases. Their findings could be the basis for future treatments for these presently incurable diseases.

The IMBA scientists, working with an international team of researchers under the leadership of Josef Penninger and Javier Martinez, discovered a completely new fundamental mechanism that triggers the death of motor neurons. "We've been working on resolving the function of the CLP1 gene in a living organism for a long time. To do that, we developed model mice in which the function of CLP1 was genetically inactivated. To our utter surprise we discovered that deactivating CLP1 increases the sensitivity of cell die when exposed to oxidative stress. That leads to enhanced activity of the p53 protein and then to the permanent destruction of motor neurons," says Toshikatsu Hanada, first author of the study.

Research group of Javier Martinez had discovered the CLP1 gene in an earlier study. Until now, the exact essential function of CLP1 in RNA biology was unclear. "By deactivating CLP1, we have discovered a previously unknown new species of RNA," says Javier Martinez about the scientific relevance of the work. "The accumulation of this RNA is a consequence of increased oxidative stress in the cell. We see this as one of the triggers for the loss of motor neurons that occurs in ALS and other neuromuscular diseases. Thus our findings describe a completely new mechanism of motor neuron diseases." Nearly all genetic mutations found in ALS patients affect either RNA metabolism or oxidative stress, suggesting a possibly unifying principle for these diseases.