Linda Crampton is an experienced teacher with a first-class honors degree in biology. She writes about the scientific basis of disease.
What Is Amyotrophic Lateral Sclerosis?
ALS, or amyotrophic lateral sclerosis, is a progressive neurodegenerative disease that has serious and often heartbreaking effects. As the disease progresses, the patient gradually loses their ability to move, speak, chew, swallow, and breathe. The patient usually dies prematurely due to death of motor neurons and respiratory failure. The disease is poorly understood and current treatments are not very effective. Researchers have discovered some intriguing facts that may be helpful in understanding and treating the disease, however.
One very interesting area of research with respect to ALS is the role of glial cells, especially astrocytes. Glial cells are abundant in the nervous system but have traditionally been considered to be less important than neurons, the cells that conduct nerve impulses. The glial cells actually play vital roles in keeping neurons alive and in enabling them to function properly. Malfunctioning astrocytes may cause or contribute to ALS.
Amyotrophic lateral sclerosis is of particular interest to me because my mother died from the disease. The latest discoveries are too late to help her, but they might be very helpful for other patients. The discoveries are interesting scientifically and medically.
The term "motor neuron disease" (or motor neurone disease) sometimes has the same meaning as amyotrophic lateral sclerosis. According to the list in the NIH reference at the end of this article, however, ALS is a type of motor neuron disease. Other diseases in the category have been identified.
The Importance of Glial Cells
There are two major types of cells in the human nervous system: neurons and glial cells. The neurons transmit nerve impulses, which are travelling electrochemical signals. These signals are essential in order to keep us alive. Neurons need the help of glial cells in order to do their job, however.
Glial cells surround neurons. The word “glial" is derived from a Greek word meaning “glue." When glial cells were first discovered, it was thought that their function was simply to hold neurons in place. Until recently, most scientists investigating the nervous system studied neurons instead of glial cells, since neurons were thought to be far more important. Researchers now know that glial cells have many essential functions. The brain actually contains more glial cells than neurons.
Glial cells are also called neuroglia, or simply glia. They support and protect the neurons, supply them with nutrients, and maintain a suitable chemical environment for them. One type—the astrocyte—also influences the behaviour of neurons. Researchers are discovering that damage to astrocytes may contribute to or even cause at least some cases of amyotrophic lateral sclerosis.
Neurons and Synapses
The three main parts of a neuron are the dendrites, the cell body, and the axon. The dendrites receive a nerve impulse from either a sensory receptor or another neuron and then send the impulse to the cell body. The cell body, which contains the nucleus and other organelles of the neuron, sends the impulse to the axon. The axon then transmits the impulse to the next neuron or to a muscle or gland. A “nerve” is a bundle of axons.
A chemical called a neurotransmitter is produced by the end of a neuron and stored in sacs called synaptic vesicles. When a nerve impulse reaches the area, neurotransmitter molecules are released from the vesicles. The molecules then travel across the tiny space that exists between neurons and bind to receptors on the next neuron. This union triggers—or sometimes inhibits—a nerve impulse in the second neuron. The region where one neuron ends and another begins is called a synapse.
Many astrocytes are shaped like a star and have tentacle-like projections that connect to neurons. They are frequently associated with synapses and have many functions, including the ones described below.
- Astrocytes supply neurons with a range of nutrients.
- They also control the concentrations of ions around the neurons.
- At a synapse, the astrocytes absorb and break down glutamate. Glutamate is an important neurotransmitter in the nervous system. A high concentration of glutamate is toxic to nerves, however.
- Astrocytes make and secrete their own version of neurotransmitters, which are known as gliotransmitters. The exact functions of these gliotransmitters aren't yet known.
- Astrocytes play a role in controlling blood flow to the brain.
An increasing number of astrocyte functions are being discovered, although the exact ways in which they act are not always clear and some of the proposed functions are controversial. For example, one claim is that astrocytes control memory and learning in the brain, which not all scientists support.
The discovery of the importance and multiple functions of astrocytes has led some scientists to refer to a "tripartite" synapse. This involves the presynaptic neuron, which releases a neurotransmitter, the astrocyte, and the postsynaptic neuron, which receives the neurotransmitter. All parts of the synapse are considered to be equally important in the tripartite model.
The Central and Peripheral Nervous Systems
The body’s central nervous system (CNS) consists of the brain and spinal cord. The peripheral nervous system (PNS) consists of nerves that travel in and out of the central nervous system, connecting it to other areas of the body. Astrocytes are located in the central nervous system. They outnumber the neurons there and are the most abundant cells in the CNS.
ALS and Motor Neuron Degeneration
Amyotrophic lateral sclerosis is also known as Lou Gehrig’s disease after the New York Yankees baseball player who suffered from the illness. There are two categories of the disease:
- familial ALS, which is inherited (accounts for about 10% of ALS cases)
- sporadic ALS, which is not inherited (accounts for about 90% of ALS cases)
Both cases involve damage to motor neurons. Motor neurons control the muscles that enable us to move as well as the ones involved in breathing, speaking, chewing, and swallowing.
Both upper and lower motor neurons may be involved in ALS. The upper motor neurons originate in the brain and are unable to leave the central nervous system. The dendrites and cell body of an upper motor neuron are located in the cerebral cortex, but the axon travels down through the brain into the brainstem or spinal cord. The axon of the upper motor neuron then stimulates a lower motor neuron. The dendrites and cell body of the lower motor neuron are located in the central nervous system. The axon extends out of the CNS and travels to the muscles in a peripheral nerve.
In ALS, upper and/or lower motor neurons degenerate and die. Strangely, some motor neurons don’t degenerate, including the ones that control the urinary bladder and large intestine. The person’s mental faculties are also unaffected in many cases, although some people with ALS develop dementia. Most patients develop the disease in their forties and older, although younger people can also be affected.
Multiple researchers are discovering evidence that astrocyte problems may be involved in ALS. The topic could be a very important area of research.
Astrocytes and Excess Glutamate
An abnormally high concentration of glutamate around neurons has been strongly implicated in the development of amyotrophic lateral sclerosis. The ALS Association says that "abundant evidence" links a high glutamate level to destruction of motor neurons. The only drug recommended for ALS treatment at the moment with respect to extending lifespan is Riluzole. (A second drug has recently become available in the United States, as described below.) Riluzole is believed to work by stimulating glutamate removal from the area around the synapses. The glutamate is normally absorbed by astrocytes. Failure of the astrocytes to do this could be linked to ALS.
Astrocytes and the SOD1 Enzyme
Researchers have discovered that mutated astrocytes present in some patients with familial ALS can cause degeneration and death of motor neurons. The mutated astrocyte gene that has been most studied is the one that normally programs the cell to make an antioxidant enzyme called superoxide dismutase, also known as the SOD1 enzyme.
In lab experiments, motor neurons die when they are cultured with the mutant astrocytes. Other types of neurons in the culture aren’t damaged. In one experiment, mutated astrocytes were grown separately. Some of the growth medium surrounding the astrocytes was then transferred to a container of motor neurons. The neurons died after they were exposed to the medium, suggesting that a toxin was made by the mutated astrocytes. Discoveries in the Iaboratory don't always apply to intact organisms, but they sometimes do.
More Evidence Linking Astrocytes to ALS
Other researchers have made intriguing discoveries linking astrocytes to ALS. In 2016, researchers found evidence suggesting that a change in the cell membrane composition of a neuron increases the damage by astroyctes.
The membrane of a neuron has a protein called Major Histocompatibilty Complex 1 or MHC1 on its surface. The researchers discovered that there was a "dramatic" loss in the amount of MHC1 in the spinal cord of people with ALS. A decreased level of the protein was also observed in lab animals with a condition resembling ALS as well as in isolated cells from these animals and from human patients.
The researchers found that in lab containers, human and animal neurons with a reduced amount of MHC1 were very susceptible to damage by astrocytes. The animals with the condition experienced "markedly extended survival" when their level of MHC1 was increased. In addition, motor neurons from ALS patients experienced reduced astrocyte toxicity when their level of MHC1 was increased. Whether this effect will also occur inside the human body is unknown. The researchers may have made a significant discovery, however.
We knew from past research that ALS astrocytes were responsible for killing motor neurons. Now we have another piece to the puzzle.
— Dr. Brian Kaspar, Nationwide Children's Hospital and the Ohio State University College of Medicine
Missing Introns and Reactive Astrocytes
In 2021, new discoveries related to astrocytes in ALS were announced by researchers at the Francis Crick Institute and University College London. The discoveries were related to reactive astrocytes in ASL, or ones whose behaviour has changed. The behaviour change was caused by the loss of introns in the RNA (ribonucleic acid) inside the astrocytes.
Introns and Genes
Unlike the rest of an RNA molecule, introns are non-coding sections (that is they, they don’t contain instructions for making a protein). The coding sections are known as genes. Introns are important despite their lack of genes because they exert control over coding genes.
The Process of Transcription
DNA (deoxyribonucleic acid) contains the original copy of the genes and the introns. The molecule is located in the nucleus of a cell. The instructions in the DNA—including those in the introns—are copied onto messenger RNA molecules in a process called transcription. These molecules then travel out out of the nucleus and go to the ribosomes. Here they direct the production of the protein coded for in the DNA.
The Splicing Process
The introns in the RNA are normally removed as the molecule matures in a process called splicing. Scientists have discovered that some introns are retained in the RNA of healthy astrocytes, however. The researchers say that when introns that normally stay are removed from the RNA of astrocytes, the cells behave abnormally. The coding section of the abnormal molecule directs the production of proteins that cause the healthy astrocytes to change into reactive ones. Reactive astrocytes have been implicated in ALS.
Astrocytes employ IR (intron retention) to post-transcriptionally repress reactivity genes; however, ALS astrocytes undergo augmented splicing and lose this homeostatic regulation, which may be an initial compensatory mechanism that may become maladaptive over time.
— Oliver J, Ziff et al, Oxford Academic
Treating the Disease Today
Medications used to treat the symptoms of ALS can help a patient feel more comfortable. Physical therapy and breathing aids may also be helpful for patients. Riluzole slows the progression of the disease in some patients. Clinical trials are being performed with other drugs that may be helpful.
In May, 2017, the FDA (Food and Drug Administration) approved a new drug for the treatment of amyotrophic lateral sclerosis.This is only the second drug that the organization has approved for the disease and the first approval in this area for over twenty years. The drug is known by the genetic name edaravone and the brand name Radicava. According to the medication's creator, it reduces the rate of functional decline in ALS patients by about a third when given to patients in the early stage of the disease. It became available for patients in the United States in August, 2017. It was approved by Health Canada in October, 2018.
At the moment, the average survival time for an ALS patient after diagnosis is two to five years. (This doesn't take into account the effect of the new medication.) An average survival time means that some people live for a shorter time and some people for a longer one. One of the things that I find sad about this survival prediction is that it hasn't changed since my mother died from the disease, which happened over thirty years ago. There is far more research being done today than when my mother was alive, however. This research could lead to some very useful developments.
Stem Cell Treatment in the Future
In lab experiments, scientists have triggered stem cells to become motor neurons. A stem cell is an unspecialized cell that has the ability to develop into other cell types. The goal of the research is to implant motor neurons created from stem cells into ALS patients (or other patients with motor neuron damage) in order to replace their own neurons. This procedure has been carried out successfully in mice, but trials in larger animals and in humans have not yet been done. One problem with this potential treatment is that if we don’t discover what destroyed the neurons in the patient’s body, the new, transplanted neurons could become damaged as well, just like the original ones.
Some scientists are working on creating astrocytes from human stem cells and feel that this a better plan of action than creating motor neurons from the cells. They know that astrocytes have a large effect on the health of motor neurons. It would also be easier to add new astrocytes to a patient's body than to add new motor neurons.
In the not-too-distant future, motor neurons or astrocytes made from stem cells, effective drug therapy to control excess glutamate, or ways to increase MHC1 might be breakthrough treatments for ALS. New discoveries about the disease mechanism may lead to additional treatments.
Stephen Hawking: A Conundrum
One famous ALS survivor was the physicist Stephen Hawking. He was born on January 8th, 1942, and developed the disease when he was only 21 years old. According to sources that should be reliable, he received a medical diagnosis of the amyotrophic lateral sclerosis form of motor neuron disease. He suffered from the condition for 55 years. His symptoms slowly worsened over time, however.
For much of his life with the disease, Hawking used a wheelchair to move around and needed special equipment in order to communicate with others. His mind remained active and he made some important discoveries in theoretical physics and cosmology. He was often described as "brilliant". He died on March 14th, 2018.
Stephen Hawking's long life with ALS was unusual. One of the people from my local ALS society who helped my mother also had a very slowly progressing form of the disease, however. Some researchers think that there are more than two types of amyotrophic lateral sclerosis, and others think that the condition may actually be more than one disease.
Treating the Disease in the Future
Many researchers study the functioning of neurons. This is understandable, because if the neurons become inactive we become incapacitated or die. I think that the functions of the glial cells mustn't be overlooked, however. Research indicates that their activity is vital for maintaining the health and activity of the neurons.
Fortunately, the role of astroyctes in ALS is still being investigated and evidence of the connection is still appearing. Whether astrocytes are the only cause of the disease or just a contributor to the illness in some, many, or all patients, I hope the research continues and is soon helpful for patients. Hopefully, researchers will soon be able to tie the different discoveries about astrocytes together and come up with a coherent picture of what is wrong with them in ALS. Perhaps this will eventually lead to an effective treatment for the illness.
I've been following the research about amyotrophic lateral sclerosis ever since my mother had the condition. I'm pleased to see more attention being paid to the disease by both researchers and the public. The movie about Stephen Hawking's life ("The Theory of Everything") and the Ice Bucket Challenge to raise funds for ALS patients and research are both great forms of publicity. In the challenge, a volunteer agrees to have a bucket of icy water poured over their head. The goal is to promote awareness of the disease and to encourage donations.
The human nervous system is complex and understanding how it operates is difficult. The interest in glial cells, stem cells, and ALS seems to be increasing, however. Hopefully, people with neurodegenerative problems will soon be able to benefit from new discoveries.
- Motor Neuron Diseases Fact Sheet from the National Institutes of Health (NIH)
- Types of glia from the University of Queensland Brain Institute
- Disease mechanisms from the ALS Association
- Interplay between astrocytes and motor neurons in ALS from the Proceedings of the National Academy of Sciences of the United States of America
- Loss of MHC1 in motor neurons leads to ALS astrocyte toxicity from the EurekAlert news service
- Harmful astrocyte changes in amyotrophic lateral sclerosis from the Medical Xpress news service
- Reactive astrocytes in ALS display diminished intron retention from Oxford Academic
- FDA approves new drug to treat ALS from Scientific American (Preview)
This content is accurate and true to the best of the author’s knowledge and does not substitute for diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed health professional. Drugs, supplements, and natural remedies may have dangerous side effects. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.
© 2011 Linda Crampton
Linda Crampton (author) from British Columbia, Canada on February 09, 2012:
Hi, conradofontanilla. Thank you for the information and the votes. ALS seems to be such a complex disease and there's so much that isn't known about its causes. I hope that all these new theories and discoveries help scientists come up with an effective treatment. My mother died of ALS so I'm especially interested in this disorder.
conradofontanilla from Philippines on February 09, 2012:
Instead of Moreno et al. I meant Morales: (Morales, Y. et al. “The Pathology of Multiple Sclerosis: Evidence for Heterogeneity.” Advances in Neurology. 2006.8:28).
conradofontanilla from Philippines on February 09, 2012:
I read your exciting Hub after I have posted my Hub "How To Treat Motor Neuron Disease Also Called Amyotrophic Sclerosis (ALS)." Cummings says that a mutated allele induces mutation in its normal allele (Cummings, M. Human Heritage, Issues and Principle. 2009). This could be the reason why mutated "motor neurons die when they are cultured with the mutant astrocytes" as you have said. Moreno et al. say that death of axons is autoimmune mediated. Autoimmunity, in the framework of free radical theories of disease, is caused by free radicals and reactive oxygen species. This framework and stem cell therapy offer much for the relief from and ALS and the heritable one, familial or FALS. Voted up and useful.
Linda Crampton (author) from British Columbia, Canada on June 26, 2011:
Thanks for the visit and comment, GarnetBird.
Gloria Siess from Wrightwood, California on June 25, 2011:
Very professional Hub!!
Linda Crampton (author) from British Columbia, Canada on June 03, 2011:
Thank you very much for the comment and the vote, Danette. I agree with you - the brain is very interesting to study!
Danette Watt from Illinois on June 03, 2011:
Another interesting and well-written hub. The brain is so fascinating to read about! Voted up and useful.
Linda Crampton (author) from British Columbia, Canada on June 03, 2011:
Thanks very much for the visit and comment, neakin! It's great to meet you.
neakin on June 03, 2011:
Very informative hub! Keep up the awesome work! Thanks!
Linda Crampton (author) from British Columbia, Canada on May 30, 2011:
Thank you very much for your comment and rating, Chatkath!
Kathy from California on May 30, 2011:
Wow, now this is an informative hub, you actually make a complicated process seem very simple and easy to understand. Good Job!! Rated up.