Dr. Janice Robertson, University of Toronto
A team of Canadian ALS researchers at the University of Toronto published a study entitled “Targeting of Monomer/Misfolded SOD1 as a Therapeutic Strategy for ALS,” in the June 27, 2012 issue of The Journal of Neuroscience. This work identifies how specific, targetable species of SOD1 are responsible for disease and demonstrates that their effective neutralization can significantly alter disease in an ALS mouse model.
Approximately 10-20 per cent of hereditary ALS is caused by mutations in the protein superoxide dismutase 1 (SOD1), though more recent work has revealed that SOD1 may be implicated in some percentage of non-genetic ALS, which makes up more than 90 per cent of cases. All proteins have a specific, three-dimensional shape (often referred to as its protein “fold”) that is necessary to perform their normal function. Through decades of studying SOD1, it has been discovered that mutations cause the structure of SOD1 to be altered leading to a misfolded form of the protein.
SOD1 only functions normally when it is paired with itself in an interaction called a dimer. In 2007, studies performed in the laboratory of Avijit Chakrabartty, PhD, revealed that when SOD1 is diseased, leading to its misfolding, one of the first steps in the process is separation of this dimer. De-dimerization unveils a region deemed SOD1 exposed dimer interface (SEDI), which is normally buried in the place where the two SOD1 stick together. By focusing the immune response on that spot, there is potential to neutralize diseased SOD1 at the very earliest stage before it has a chance to have any toxic effects.
Utilizing this knowledge, Janice Robertson, PhD at the Tanz Centre for Research in Neurodegeneration, (who collaborated along with Chakrabartty and Neil Cashman, MD on the original SEDI work) has now demonstrated that mice could be immunized with a piece of protein mimicking this SEDI region, to produce antibodies against misfolded SOD1 and that this both delayed disease onset and extended disease duration in an ALS mouse model. This was correlated to an overall reduction in the amount of many toxic SOD1 forms. According to Robertson, this “provides the first evidence for the neurotoxicity of monomeric/misfolded SOD1 in vivo (in a living animal) and validates these species as legitimate therapeutic targets for the treatment of SOD1 associated ALS.”
One critique about stimulating the immune system for ALS therapy is the concern over producing an inflammatory response that could either exacerbate the disease or cause dangerous side effects such as meningoencephalitis that plagued early attempts in Alzheimer’s disease. Fortunately, the immunization strategy used here favoured a non-inflammatory, protective response; a good sign for its potential to someday move into the clinic.
The poor ability of antibodies to cross the blood-brain barrier has also been seen as an obstacle for this type of therapeutic approach. However, one of the key aspects of Robertson’s work, compared to others, is that the site attacked by the immune system, the aforementioned SEDI region, is known. Such knowledge gives a target for screening of drugs that could potentially perform the same task as antibodies, but can more readily enter the brain for greater therapeutic effect.
The authors conclude that “Our results support that SOD1 misfolding/aggregation plays a central role in S0D1-linked ALS pathogenesis and identifies monomeric/misfolded SOD1 as a therapeutic target for SOD1-related ALS.
To download a copy of the paper please click here:: http://www.jneurosci.org/content/32/26/8791.abstract