Amyotrophic lateral sclerosis (ALS) is a disease surrounded by a lot of mystery and frustration as the mechanisms of the disease are not fully understood, and there is no current way to cure, or even truly successfully treat the disease. ALS is a fatal disease characterized by degeneration of upper and lower motor neurons. Most patients with ALS end up dying of respiratory failure as their diaphragm is no longer able to function to help them breathe. Once patients are diagnosed, they are usually given a life expectancy of around two years. There is some hope though, as there have been certain people, like Stephen Hawking, who live for decades with the disease, we just have to figure out what to treat.
There are a couple main target points in the body that researchers have found to be associated with ALS. One is mutation of the SOD1 gene, which normally functions to protect the body from metabolic waste. ALS has been found to be associated with high oxidative stress in the body as well. This may be partly due to dysfunction of the SOD1 gene. It also appears to affect two RNA binding proteins, FUS and TDP43, not allowing them to properly function in RNA metabolism, affecting the functionality of other proteins in the body. The decreased function of these proteins may also lower the body’s ability to protect it from oxidative stress. Oxidative stress is also hurting mitochondrial function by affecting its proteins and metabolism. Thus, these two possible mechanisms seem to cross-over with each other.
One big question about the disease is why it only seems to cause degeneration of the motor neurons specifically?
I have come up with 5 possible reasons from looking at some research done by the ALS association:
1. Axon structure and proteins – motor neuron axons are around a meter long. This is a long way to transport messages, it would have high metabolic demands, and there is a lot of room for proteins associated with it to be affected making it harder to protect.
2. Too much cell apoptosis – even cell death that is programmed by the body can be harmful if it is happening too much. Possible halting some of the apoptotic events is being studied by scientists to possibly help the neurodegeneration.
3. Mitochondria – the motor neuron is huge and requires a lot of energy to stay functional. The mitochondria provides energy to its neuron, and as the mitochondria becomes dysregulated or dysfunctional, the motor neuron will lose its ability to function.
4. Glutamate – this is the main excitatory neurotransmitter of the body. Too much excitatory activity of a cell can lead to cell death, and in ALS there may be too much glutamate around and acting on the motor neurons.
5. Inflammation – this immune system process often happens as a result of cell death. If there is too much apoptosis going on or motor neurons or their surrounding cells dying from excitotoxicity, inflammation may be upregulated further damaging and killing more motor neurons.
Obviously there is no solid answer right now of the ALS disease mechanism. Maybe solving the “motor neuron mystery” will be key in treating ALS. It will be important to keep people aware of this disease, and keep research moving forward.
The Mystery of ALS: Motor Neurons
