New genetic risk factor for Lou Gehrig's disease discovered An international team of scientists working at the University of Pennsylvania, US and Goethe University in Germany has identified a new genetic risk factor for amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease after the US baseball player died from th... An international team of scientists working at the University of Pennsylvania, US and Goethe University in Germany has identified a new genetic risk factor for amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease after the US baseball player died from the rare brain disorder at only 38. EU support for the research came from the EUROSCA ('European integrated project on spinocerebellar ataxias') project, which received over EUR 9 million from the 'Life sciences, genomics and biotechnology for health' (LIFESCIHEALTH) Thematic area of the EU's Sixth Framework Programme (FP6). The findings are published in the journal Nature. ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. Experts say 1 or 2 out of 100,000 people develop ALS each year. The disorder most commonly strikes people between 40 and 60 years of age, but younger and older people can also develop it. ALS generally progresses rapidly and is invariably fatal, attacking the nerve cells responsible for controlling voluntary muscles - the muscles gradually weaken and then waste away. Eventually the brain loses the ability to control voluntary movement and when the muscles in the diaphragm and chest wall fail, sufferers become unable to breathe without ventilator support. Any progress towards understanding this devastating disease for which there is currently no cure is obviously hugely welcome and scientists, led by Dr Aaron Gitler at Penn's School of Medicine, believe they have done just that. Using yeast and fruit flies as models before following up with human DNA (deoxyribonucleic acid) screening, the team found evidence that mutations in the ataxin 2 gene were a genetic contributor to the disease. In particular, the study showed that repetitions of the amino acid glutamine in ataxin 2 (called expansions) were associated with an increased risk of ALS, with a frequency of 4.7 % of ALS cases examined. The researchers said the 'identification of pathological interactions between ataxin 2 and TDP-43, another ALS-associated disease protein, together with the strong genetic association of glutamine expansions in ataxin 2 and ALS, should aid in the development of biomarkers and empower the development of new therapies for this disease'. The team began by identifying genes that could suppress or enhance TDP-43 toxicity in yeast. Among the genes that modified toxicity was the yeast counterpart of ataxin 2. They then transferred the genes to the fruit fly to assess effects of the genes and their interactions in the nervous system. The results indicated a link between the proteins and the disease. For example, when the researchers directed expression of TDP-43 to the eye of the fruit fly, a progressive, age-dependent degeneration began, and when directed to the motor neurons, flies experienced a progressive loss of motility. The higher the levels of ataxin 2, the greater the toxicity of TDP-43 and the worse the degeneration. 'Because reducing ataxin 2 levels in yeast and flies was able to prevent some of the toxic effects of TDP-43, we think that this might be a novel therapeutic target for ALS,' said Dr Gitler. The researchers extended these findings to determine whether ataxin 2 showed alterations indicative of an association with ALS. They found that ataxin 2 appeared altered in spinal cord neurons from ALS patients. Following this up with analysis of the type of mutation that is found in ataxin 2 in its other disease, spinocerebellar ataxia 2 (or SCA2, another glutamine expansion), they showed a link between expanded ataxin 2 repeats and risk for ALS. 'There have been previous hints of similarities between ALS and SCA2,' noted Michael Hart, a Penn graduate student in Gitler's laboratory and co-author of the study. 'Our findings suggest a molecular explanation for these similarities and raise the possibility that treatments for one disease might be effective for the other.'