Amytrophic lateral sclerosis (ALS), otherwise known as Lou Gehrig’s disease, is a disease which appears in adults and affects motor neurons. There are two different forms, of which sporadic ALS is by far the most common. It now appears that an imbalance of calcium could play a huge role in the pathogenesis of ALS. A variety of proteins and transport mechanisms exist to ensure that the appropriate levels of calcium are in various cellular organelles, namely the endoplasmic reticulum, which is important in modifying proteins as they are produced, and the mitochondria, which is important in energy production for the cell. When inappropriate levels of calcium are in the endoplasmic reticulum, ER stress occurs and a mechanism called the unfolded protein response is activated in response. In ALS, too much calcium is taken out of the ER and put in the mitochondria, and so proteins are not folded properly in the endoplasmic reticulum, and the increased levels in the mitochondria can have a variety of detrimental effects such as defects in energy metabolism, the generation of reactive oxygen species (which are not good things to have around, and are part of the reason it is so good for us to consume things high in antioxidants like green tea), and the activation of apoptosis (which ultimately means cell death). As a result of these abnormalities in motor neurons, the motor neurons die, and we see ALS. The reason only motor neurons are affected in ALS is due to a certain kind of receptor motor neurons have called an AMPA receptor. When the neurotransmitter glutamate is released, it binds to AMPA and allows calcium into the cell and throws everything out of balance. AMPA receptors on the motor neurons of those with ALS lack a certain component which results in more calcium being allowed into the cell.
There are a number of different molecules and mechanisms that also play a role in regulating calcium levels in the cell, and thus provide targets for treating ALS. Of course, as always, we must add in the caveat that it is much more complicated than it appears at first glance to actually treat this, as we don’t want to affect other pathways that use the same molecules and/or mechanisms. As ALS affects motor neurons, it should come as no surprise that these molecules also play a large role in things like muscle contraction, and so we have to be careful to not harm that by going too far with modifying the levels of all of these molecules in the body.
There is also the issue that it is currently somewhat unknown whether misfolded proteins are misfolded because the motor neurons have degenerated, or if the motor neurons degenerate because the proteins are misfolded. There are many things that remain to be known about this, but at least we are starting to make good headway in starting to learn what exactly is going on in the spinal cord of patients with ALS.
ALS… Making Progress Towards Understanding
