- The 23rd International Symposium on ALS/MND, held in Chicago on Dec. 5-7, 2012, gathered some 900 ALS delegates from around the world to share data and ideas.
- The conference featured reports on current ALS research, including SOD1, C9ORF72, and genetic and nongenetic risk factors.
The 23rd International Symposium on ALS/MND (motor neuron disease), held in Chicago Dec. 5-7, 2012, brought together more than 900 researchers, clinicians and other health care professionals from 30 countries to hear presentations on the latest in ALS care and research.
Among the presentations were research updates on a number of topics, including the SOD1 gene and protein, the C9ORF72 gene, and genetic and nongenetic risk factors in amyotrophic lateral sclerosis (ALS).
SOD1 in familial and sporadic ALS
Mutations in the SOD1 gene, first identified as a cause of familial ALS in the early 1990s, result in the production of any number of varieties of improperly folded SOD1 protein.
But recent evidence shows that this phenomenon isn’t restricted to SOD1 protein made by a mutated SOD1 gene. It now appears that even normal SOD1 protein has a propensity to misfold, after which it induces misfolding in neighboring SOD1 protein molecules, reported Neil Cashman, a clinical neurologist and neuroscientist at the Brain Research Centre, University of British Columbia in Vancouver, British Columbia, Canada.
The propagation of misfolded SOD1 protein in the body appears to drive cell-to-cell and region-to-region spread of ALS in both the familial and sporadic forms of the disease, Cashman said.
Cashman, who has long hypothesized that misfolded SOD1 molecules are tied to the spread of weakness in ALS, is working on the development of misfolding-specific antibodies to target improperly folded SOD1 and block the process.
For more about SOD1 in ALS, see:
- ISIS-SOD1-Rx Well-Tolerated, MDA/ALS Newsmagazine, Dec. 13, 2012
- ALS: SOD1 Protein Can Cause Trouble Even When It’s ‘Normal’, MDA/ALS Newsmagazine, Oct. 26, 2012
- Misfolded SOD1 Found in Sporadic ALS Samples, MDA/ALS Newsmagazine, Oct. 19, 2012
- Familial, Sporadic ALS Linked Via Astrocytes and SOD1, MDA/ALS Newsmagazine, Aug. 29, 2011
- SOD1 Causes Toxicity in Some Familial and Some Sporadic ALS, MDA/ALS Newsmagazine, April 13, 2012
C9ORF72: The story continues
In September 2011, two independent research teams identified an ALS-causing mutation in the C9ORF72 gene. The mutation is an abnormally large, repeated section of DNA called a repeat expansion.
In December 2012, the significance of that finding was acknowledged when Rosa Rademakers, who led one of the two teams that uncovered the C9 mutation, was awarded the 2012 Paulo Gontijo Young Investigator Award for her work on C9.
Rademakers, an associate professor of molecular science at the Mayo Clinic Florida in Jacksonville, provided an overview of both the C9 discovery and current C9-related research going on around the world.
In addition, Mariely de Jesus-Hernandez, a member of Rosa Rademakers’ lab, talked about one of the latest C9 findings — that the repeat expansion in the C9 gene differs in length in different types of cells, a phenomenon called somatic instability. (The length of a repeat expansion reflects the number of times a DNA sequence is repeated.)
De Jesus-Hernandez presented data showing that the mutation’s repeat length varies depending on where it’s located. The mutation’s length in the spleen, heart, muscle and blood differs from that in the liver and also from that in the central nervous system.
It’s also possible, de Jesus-Hernandez said, that the mutation’s repeat length may vary in a particular tissue at different times.
The reasons for the instability aren’t yet known, and it isn’t possible at this time to accurately measure repeat lengths. However, the findings could have implications for diagnostic testing and the conduct of experiments and clinical trials. Differences in repeat lengths between mutated C9 genes found in blood and brain cells, for example, would need to be considered when performing studies that involve the relation of repeat sizes to clinical or disease characteristics.
Antisense against C9ORF72
Mutated C9ORF72 genes are being targeted by a form of gene therapy called antisense oligonucleotides (ASOs) that’s designed to inactivate the genes, or the repeat expansions they harbor.
Jeffrey Rothstein, director of the Johns Hopkins Brain Science Institute and Packard Center, and the MDA/ALS Center, both at Johns Hopkins University, discussed using ASOs to stop the effects of toxic RNA, boost gene activity (expression) and change the genetic instructions that cells use when making proteins.
Using induced pluripotent stem cells (iPS cells) derived from people with C9ORF72-related ALS, Rothstein and colleagues are testing two methods to counteract the gene's toxic effects. One way is to block the repeat expansion from being formed in the first place; the second is to block the entire gene.
Rothstein reported that results show ASO-based therapy can decrease C9 expression, without toxicity, in a cell model of ALS. It also is able to normalize the harmful changes (upregulated and downregulated gene expression) brought about by the C9 mutation.
Risk factors for ALS
Ammar Al-Chalabi from King’s College, London, talked about research into the causes — genetic, possibly nongenetic and perhaps even chance — of ALS.
Among the potential causes, Al-Chalabi noted, are the genes we carry, what happens to us during our lifetime and randomness. Despite a great deal of research, however, no proof has yet emerged that people’s behavior affects their chances of getting the disease, and it’s unknown if a person’s ALS can ever be completely “random.” Genes have been identified as some of the causes of the disease, but it’s unknown how much of a role they play in ALS processes later on. One conclusion Al-Chalabi offered is that nature, nurture and genetics all likely play a part in ALS — and they probably interact.
Determining the causes of, and influences on, ALS is important, Al-Chalabi noted, for helping in the design of new treatments, for possibly allowing people to avoid behavior that could increase risk, and for helping people grapple with one of the first questions they ask after receiving a diagnosis of ALS: Why me?
Note: A multipart article on nongenetic risk factors for ALS is scheduled for publication in the online MDA/ALS Newsmagazine in January 2013.
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