ALS: Gene Mutation, Protein Misfolding, and a Possible Treatment
Linda Crampton is a writer and teacher with a first class honors degree in biology. She often writes about the scientific basis of disease.
Amyotrophic Lateral Sclerosis, or ALS
Amyotrophic lateral sclerosis can be a devastating disease, as I unfortunately know from experience. My mother died from the illness. The condition is also known as ALS, motor neuron or motor neurone disease, and Lou Gherig's disease. Gherig was a famous New York Yankees player who suffered from the illness. ALS is proving to be a very difficult condition to understand and to treat. An exciting discovery at Oregon State University may lead to an effective treatment for at least some cases of the disease, however.
ALS is a neurodegenerative condition in which motor neurons are harmed and stop functioning. These neurons, or nerve cells, control movement, swallowing, speaking, and breathing. The patient develops problems with all these abilities, but in many patients the cognitive abilities of the brain are unaffected. Death is generally a consequence of breathing problems. Most patients die within two to five years of diagnosis.
Technically, the term motor neuron disease refers to a group of diseases involving the degeneration of motor neurons. In North America, though, it's nearly always synonymous with amyotrophic lateral sclerosis. In the UK, ALS is known as motor neurone disease.
Stephen Hawking and Motor Neurone Disease
Stephen Hawking is probably the first person that many people think of when they hear the term ALS, or motor neurone disease as it's called in Britain. Hawking was a famous physicist who was diagnosed with the disease at the age of 21. He lived with amyotrophic lateral sclerosis for fifty-five years. He died on March 14th, 2018. His long lifespan with the disease is amazing. He had a very slowly progressing form of the illness that appeared at a relatively early age. In most ALS sufferers, the disease appears in middle age or later and progresses rapidly.
Hawking's condition gradually worsened. For much of his life with the disease, he was confined to a wheelchair and needed special equipment in order to communicate. He kept exploring theoretical physics, however, and made some interesting and important proposals about the nature of the universe. His case offers hope to other patients and also illustrates our lack of understanding of the disease.
The Nervous System
Finding a Cure for ALS
It's very hard to create a treatment or a cure for an illness when we don't understand its cause. There are still many unanswered questions about the development of ALS. Researchers continue to make discoveries, but the problem as I see it is that the separate discoveries can't yet be related to each other in order to make a unified whole. There are different subtypes of amyotrophic lateral sclerosis, so there may well be multiple causes of the disease and different processes that lead to similar symptoms.
Until 2017, the only drug known to extend life for ALS patients was riluzole (brand name Rilutek). The drug only works in some people and only lengthens life for a few months. It's thought to lower the high level of glutamate in the central nervous system. Toxicity to nerves from excess glutamate is one of the proposed causes of ALS. Glutamate may be a factor in the disease, but we need to find the primary cause in order to create a truly effective treatment.
In 2017, the FDA (Food and Drug Administration) approved a new medication for treating ALS. Its name is edaravone (brand name Radicava). A clinical trial has shown that it slows the rate of symptom progression by about a third. It's believed to work by reducing oxidative stress. This condition is caused by the buildup of free radicals, which are harmful at high concentrations.
An Overview of Amyotrophic Lateral Sclerosis
The video above refers to the Ice Bucket Challenge for ALS. In this event, volunteers agree to have icy water thrown over them and to be filmed while this happens in order to raise awareness for the disease. Another goal of the event is to raise money for ALS research.
Familial and Sporadic ALS
Amyotrophic lateral sclerosis is most commonly classified as either familial or sporadic. As its name suggests, familial ALS runs in families and is believed to be caused by a mutated gene. Sporadic ALS appears for no known reason, although it's thought to be due to a combination of a genetic problem and an environmental trigger. About ninety percent of ALS cases are sporadic.
DNA, or deoxyribonucleic acid, is located in the nucleus of a cell. The order of nitrogenous bases on one strand of a DNA molecule provides instructions for making proteins.
A protein-coding gene is a section of a DNA molecule that contains the instructions for making a specific protein. The instructions are encoded in a series of chemicals known as nitrogenous bases. When a gene mutates, the order or identity of the nitogenous bases is altered. As a result, the code is changed and an altered protein is made (if it can be made at all). Like the gene, the altered protein is often said to be mutated.
The SOD1 Protein and Amyotrophic Lateral Sclerosis
Familial ALS has frequently been linked to a mutation in the gene that codes for a protein called copper, zinc superoxide dismutasase. This protein is also known as SOD1. SOD1 acts as an enzyme (a protein that controls chemical reactions) and serves a very important function. It breaks down superoxide radicals. These radicals are by-products of cellular processes involving oxygen. They are dangerous because they damage cells. Cells normally remove the superoxide radicals once they form, however, so they remain safe.
In many people with familial ALS, the mutated gene for SOD1 causes an abnormal protein to be made. The mutated SOD1 protein is misfolded. Proteins are long chains of amino acids that must be folded into a specific shape in order to do their job.
Misfolded SOD1 is unable to perform its usual function. Research in mice suggests that this is not the main reason why the mutant protein is harmful, however. The mutated SOD1 protein appears to be toxic to neurons.
A protein is made of a chain of amino acids. The chain is known as a polypeptide, since peptide bonds join the amino acids together. Many proteins consist of more than one polypeptide.
The Oregon State University Research
The researchers at Oregon State University performed their experiment with a "mouse model" of ALS. The mice were genetically programmed to develop the disease and had a mutated gene for SOD1. The scientists were able to stop the progression of ALS in the mice by treating them with a chemical called Cu-ATSM. The mice went on to live an almost normal lifespan.
When the researchers stopped the treatment in one group of mice, the symptoms of ALS began to worsen within two months. If treatment wasn't resumed, the mice died. If the scientists resumed the Cu-ATSM treatment in the mice, the progression of the disease stopped and the mice survived.
The results of the experiment were clear-cut and impressive. Clinical trials must be performed to see if the same results occur in humans, however.
The Blood-Brain Barrier or BBB
Cu-ATSM is a chemical compound that is already used in medicine in low doses. It's a significant chemical because it's able to cross the blood-brain barrier. This barrier consists of a network of tiny blood vessels, or capillaries, in the brain and spinal cord. Capillaries exist throughout the body, but the ones in the central nervous system have a special feature. The endothelial cells that line the capillaries in the CNS lie much closer together than those in other capillaries. The cells form a barrier that prevents substances from leaving the bloodstream and entering the CNS.
Essential substances such as oxygen and nutrients can still pass through the blood-brain barrier using specific transport methods, but many chemicals are blocked. The barrier is important because it keeps harmful substances out of the central nervous system. However, it makes it hard for doctors to deliver medicines to the CNS. Fortunately, Cu-ATSM can cross the blood-brain barrier.
Copper-ATSM and the SOD1 Protein
At the moment, Cu-ATSM is mainly used for imaging studies. It's useful for detecting tissues that contain a low oxygen level. The new research indicates that Cu-ATSM has another useful function. It's able to deliver copper to cells in the brain and spinal cord, including the motor neurons.
Copper is an essential part of SOD1's structure. A mutated, copper-deficient form of the protein is believed to be involved in some cases of familial ALS. Without copper, the protein is unable to fold correctly.
It's thought that copper supplied by Cu-ATSM prevents the misfolding of SOD1 in a nerve cell. A protein called copper chaperone for SOD transfers the copper from the Cu-ATSM to the SOD1.
The copper from Cu-ATSM may have additional benefits within the cell. For example, it seems to improve the condition of mitochondria. Mitochondria are the organelles that produce energy for cells.
The researchers caution that ALS sufferers mustn't take large doses of a copper supplement as a self-treatment. Supplemental copper doesn't behave the same way inside the body as Cu-ATSM. In addition, ingesting copper supplements at high or even moderate doses is dangerous.
Interpreting the Results of the Mouse Experiment
The new discovery is very exciting, but we need to interpret it with some caution. First, the research was performed in genetically-altered mice, not humans. Mouse results often apply to humans, but not always.
Secondly, the discovery most obviously applies to certain cases of familial ALS and not to the more common sporadic version of the disease. SOD1 problems may or may not be involved in people with sporadic ALS. The evidence is conflicting. Another point to note is that although the treatment stopped ALS from getting worse and killing the mice, it didn't repair neuron damage that had already occurred.
On the plus side, this is not the first time that scientists have found a possible benefit of Cu-ATSM for ALS symptoms. The discovery could be excellent news for at least some ALS patients if its safety and effectiveness are confirmed.
If the treatment becomes a reality, therapeutical techniques and special equipment might be able to help patients deal with the symptoms that have already developed. In the future, researchers may find a way to improve the condition of damaged neurons. The researchers may even find a way to generate new motor neurons from stem cells and then implant them into the body of ALS patients. This strategy is already being explored.
ALS and Protein Misfolding
Dr. Cashman has made an observation that has also been made by other scientists. Once a protein is misfolded in ALS, it appears to trigger another one to misfold. This process repeats in a chain reaction like a row of dominoes collapsing.
Significance of the Discovery for Neurodegenerative Diseases
The new discovery is very interesting with respect to ALS treatment. It could also be indirectly significant for some other neurodegenerative diseases. Protein misfolding is involved in Alzheimer's disease and Parkinson's disease as well as in ALS. An understanding of why and how proteins misfold could help more than one health problem.
Researchers must demonstrate that the doses of Cu-ATSM needed to (potentially) treat ALS are safe before they can test whether it is effective. A Phase 1 clinical trail is in progress and is showing that low doses of the chemical are tolerated well by people. The researchers say that they are moving as quickly as possible. Time is of the essence when treating ALS.
The research results have attracted a great deal of attention, especially from ALS patients. People concerned about the disease have waited a very long time for an effective treatment. I hope the recent discovery is helpful for many people.
- "Amyotrophic Lateral Sclerosis (ALS) Fact Sheet." National Institutes of Health. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet (accessed September 8, 2017).
- Oregon State University. "New therapy halts progression of Lou Gehrig's disease in mice." ScienceDaily. www.sciencedaily.com/releases/2016/01/160129090449.htm (accessed September 8, 2017).
- Goldstein, Robert. "Copper Compound (CuATSM) Shows Promise in ALS Lab Studies." ALS Therapy Development Institute. https://www.als.net/news/copper-compound-cuatsm-shows-promise-in-als-laboratory-results/ (accessed September 8, 2017).
- Beckman, Joe. "An Update on Cu-ATSM and Clinical Trials for ALS." Oregon State University. http://blogs.oregonstate.edu/linuspaulinginstitute/2017/03/14/update-als-clinical-trials/ (accessed September 9, 2017).