ALS is a complex disease for which there is no known underlying cause of all cases. Since the original human genome was sequenced, genetic researchers all over the world have been applying that technology to identify “ALS genes”. To date, there have now been approximately 30 genes identified (see graph below). SOD1 being the first to be identified in 1993 and TUB4A was announced as the 30th ALS gene in October 2014.
The exponential growth in genetics related to ALS has been increasingly helpful to researchers and scientists, such as those at the ALS Therapy Development Institute. Our scientists are actively exploiting information gained from these genetic discoveries to accelerate the discovery and development of effective treatments for ALS. This includes the creation of new models in which to screen drugs in, such as human induced pluripotent stem cell lines and mouse models, as well as potential therapeutics using antibody or antisense technology.
This summer there was a tremendous amount of attention paid to ALS in the media and as a result many stories were placed. One story that has been circulating around the internet is a troubling one about one such gene associated with ALS called Ubiquilin-2 (UBQLN2). Alterations in the ubiquilin 2 (UBQLN2) gene may trigger a rare form of ALS and ALS-dementia according to a study published in 2011. Ubiquilin-2 may help reduce misfolded proteins which typically buildup in the central nervous system in people with ALS. Researchers estimate that mutations in the gene explain less than 1% of inherited cases of the disease (FALS). The discovery adds to growing evidence that accumulation of misfolded proteins contributes to ALS.
The original findings, published by Northwestern University, were interesting and added weight to the hypothesis that ALS is hastened perhaps due to misfolded proteins and the body's inability to properly clear them. However, the media hype around this mutant gene was quite unfortunate. It is quite clear that mutant UBQLN2 is not the cause of all ALS cases.
It is also important to note that the original findings were announced more than three years ago (in 2011). Similar announcements have been made since by other labs and there are several therapeutic approaches to specific ALS genes being pursued, including gene therapy for SOD1, antibody approaches to clearing misfolded SOD1 and TDP43 and antisense approaches to SOD1 and C9orf72, just to name a few. However, to our knowledge there are no active therapeutic aimed programs specifically targeting UBQLN2. Many of the genes associated with FALS result in misfolded proteins. Therefore, there are many therapeutic aimed projects, both in our lab and at others, that working to address the misfolding of proteins to occur in the first place and/or to augment the normal process of removing these proteins before they cause issues. Several of the therapeutic approaches mentioned here will be discussed at our upcoming Leadership Summit.
As more ALS genetics are known it is crucial that researchers and scientists (and the Institutions they are associated with) provide context. Every new gene identified brings us closer to understanding the causes of ALS. There are important research efforts taking place world-wide today to identify new ALS genes, including a major effort of Biogen Idec and the global program managed by ProjectMine.