A multiplicity of potential causes and mechanisms of action have been suggested to explain the differing phenotypes of ALS (amyotrophic lateral sclerosis or Lou Gehrig’s Disease). Since symptoms and progression vary widely in both familial (hereditary) ALS and sporadic (non-hereditary) ALS, this is not surprising. Suggested contributing factors in either form of ALS included genetic factors, biochemical factors, and cellular factors.
There has been a great deal of research on the mutations of a gene called SOD1, which is affected in 20% of familial ALS cases. Prominent mutations include G93A, A4V, G85R, and G37R. Most studies dealt with the G93A mutation, although it is not the most common form. A review of the literature showed that SOD1 mutations in general are associated with an extensive list of below-tissue-level effects. These include molecular effects such as disrupted dimerization, demetallation, metal substitution, incorrect orientation, deactivation, creation of disulfide bonds, formation of aggregates, excess cellular superoxides, and cytochrome c release or deficiency of cytochrome c oxidase.
Biochemical reactions are targeted in the case of nitric oxide dysregulation, increased activation of Rac1 and NOX, p53 activity, and increased peroxidase. Mutations can also affect the organelles inside the cell, including the mitochondria, Golgi apparatus, DNA inside the nucleus, and neurofilaments. Cellular effects can involve oxidative stress, inflammation, glutamate-mediated excitotoxicity and Kir channel reduction. Biochemical changes and cell effects have been noted in some but not all cases of ALS.
Another gene that frequently shows mutations in ALS is TDP-43. The TAR DNA binding protein -43 is important in the process of mitosis (the cell cycle), and, like mtSOD1, has a tendency to form aggregates when mutated. The aggregates may take the form of stress granules, and may involve segregation of neurofilaments. When TDP-43 is aggregated or mislocalized into the cytoplasm, its function in mitosis is compromised, and it may encourage cell death rather than reproduction. Chick embryos treated with mutated TDP-43 did not develop properly, failing to mature and lacking limb and tail buds.
Thus, a constellation of contributory factors have been identified to help explain the clinical picture of amyotrophic lateral sclerosis, whether familial or sporadic. This multi-factorial foundation accounts for the wide variation that is seen in symptoms, onset, and progression of individual ALS cases (sometimes within families as well).
However, new research at Northwestern University has discovered an underlying cause in all forms of ALS: dysfunction of the protein ubiquilin2. Neurons must break down and recycle cellular proteins that have been damaged, and ubiquilin2 is responsible for this task. When ubiquilin2 is not functioning properly, misfolded and impaired proteins remain in the motor as well as cortical neurons and form the characteristic plaques or aggregates.
Now that a common pathogenesis of all forms of ALS has been identified, further research can target ubiquilin2 for drug treatment and other therapies, giving new hope to the estimated 350,000 people around the world who are affected by this neurodegenerative disease. In fact, ubiquilin2 may prove to play a part in other diseases such as Parkinson’s and Alzheimer’s as well.
Reference:
Northwestern University (2011, August 21). Common cause of all forms of amyotrophic lateral sclerosis (ALS) discovered. ScienceDaily. Retrieved August 21, 2011, from http://www.sciencedaily.com /releases/2011/08/110821141115.htm?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+sciencedaily+%28ScienceDaily%3A+Latest+Science+News%29&utm_content=My+Yahoo