The body is the vessel through and by which we experience the world. To be unable to interact with it physically while being mentally aware is arguably the scariest thing about paralysis. ALS (amyotrophic lateral sclerosis) is a debilitating and aggressive disease involving degeneration of the motor nerves which branch off of the spinal cord and communicate with muscles, leading to their atrophy and later death. The damaged nerve tissue scars and hardens, never to regenerate. This slow, painful atrophy of muscle tissue can cause tremors, rigidity, and paralysis and affects all muscle tissue, including the muscles of the digestive system (making it nearly or completely impossible to eat or digest food) and the muscles that make up the heart (causing it to, eventually, stop beating). Despite much-needed publicity during the summer’s ice bucket challenge, the disease is still nowhere near a definitive cure. This is due mostly to how difficult it has been to isolate exactly what it is that causes degeneration, although there have been a few areas on which recent research has focused.
Glutamate excitotoxicity
The hypothesis which became the focus of our week was that one of the mechanisms causing ALS is excitotoxicity. Glutamate excitotoxicity occurs when an excess of glutamate, a chemical involved with cell signaling, builds up outside the cell and causes a host of chain reactions which ultimately result in cell death. We explored and discussed not only ways by which this event occurs, but also looked more deeply into how the cell is affected internally.
Beyond there simply being an excess of glutamate outside the cell, excitotoxicity is also contributed to when too-perfect conditions allow glutamate’s receptor to become overactive. For example, amino acids glycine or D-serine must simultaneously bind with one of glutamate’s receptors (NMDAR, AMPAR) in addition to glutamate in order for the receptor’s signal to be sent. When more glycine and serine are floating around, more signals can be sent than is normal with a similar amount of glutamate.
The receptor
NMDAR, one of glutamate’s receptors, is also sensitive to the electrical charge inside the nerve cell. Neurons fire when they reach a certain electrical charge (known as an action potential) which comes about as the result of multiple signals that gradually increase the charge in the cell. What it means for NMDAR to be sensitive to the neuron’s charge is that it will only continue to send its signal after the cell has already been brought closer to this action potential. NMDAR sends further signals into the cell by allowing calcium to rush in, bringing the neuron even closer to firing.
Inside the cell
One issue with the overaction of NMDAR is that too much calcium too often can cause detrimental effects within the cell. The endoplasmic reticulum (ER) is a structure in many cells that is mainly responsible for the production and proper folding and transport of proteins. Protein folding is important because if the protein is in the wrong shape it fails to perform its job correctly. The ER also stores extra calcium in the cell, which can either be released or “sponged up” by proteins such as calreticulin in order to prevent damage.
Connections to motor neuron death
But how much damage can calcium really cause? When there is an excess of calcium, the ER can become stressed and fail to do its job properly. This can result in misfolded or unfolded proteins. The unfolded protein response (UPR) attempts to get things back to how they’re supposed to be. If the effects of the UPR do not result in the reestablishment of homeostasis, a series of events result in apoptosis: cell death.
The mitochondrion (better known as “the powerhouse of the cell”) can go through a similar process in which calcium-related stress can lead to death of the cell.
Hope for ALS?
Every day that research is done we get one step closer to finding a cure – or at least a treatment that can improve the lives of people living with and suffering from this disease. Although we may seem too far away for hope, we’re closer than we’ve ever been. A drug called memantine (which blocks some NMDARs) has shown promising results in a mouse model for ALS. It may be soon be used in clinical trials on human patients with ALS to determine its true ability to combat the disease.
Current Progress in ALS Research
