A number of pathological mechanisms are thought to play a role in the degeneration of motoneurons in ALS.
- Prolonged excitation of motoneurons by a chemical messenger called glutamate that normally activates motoneurons in the brain and spinal cord, but which in ALS may actually overwhelm motoneurons, so that they become over-activated and die. Indeed, Riluzole, the only approved treatment for ALS, is thought to work by suppressing glutamate activity.
- Inflammation within the brain and spinal cord may be involved- since the resident immune cells of the nervous system, the microglia cells, are activated by the disease process of ALS, resulting in inflammation and the subsequent production of chemicals that are toxic to motoneurons.
- Mitochondria are the powerhouse or battery within cells that generate all their energy that cells need to carry out all their functions. Motoneurons are very energy-demanding, active cells that place a heavy demand on their mitochondria. Defects in these batteries are some of the very first changes that have been observed in motoneurons in ALS, and can be detected long before any signs of muscle weakness in mice models of ALS.
- Programmed cell death (apoptosis) is deregulated in ALS.
- A characteristic feature of almost every neurodegenerative disease, including Alzheimer’s, Parkinson’s and ALS, is the appearance of aggregates of mis-folded proteins. Proteins normally stick together when they lose their normal shape and become faulty so that they can no longer perform their normal function. Prevention of this protein aggregation is a possible strategy for treating ALS.
- Oxidative stress - Oxygen free radicals are toxic chemicals formed as a normal by-product of processes within the cell.
- Transport disruption – Motoneurons are very large cells and their fibers that contact muscles can be over a meter long. It is therefore important that their transport systems for moving nutrients, waste and components from one end to the other work well. Research suggests that in ALS, the transport system becomes disrupted very early on in the disease process. Strategies that aim to restore this transport system may be effective in treating ALS.