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ALS - Mutation, Protein Misfolding and a Possible Treatment

Updated on February 9, 2016
AliciaC profile image

Linda Crampton is a teacher with a first class honors degree in biology. She writes about human biology and the scientific basis of disease.

Diagram of a typical motor neuron
Diagram of a typical motor neuron | Source

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. A recent and 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 ALS 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, the term is nearly always synonymous with amyotrophic lateral sclerosis. In the UK, the term "motor neurone disease" is used for ALS.

Stephen Hawking and ALS

Stephen Hawking is often mentioned with respect to ALS, or motor neurone disease as it's called in Britain. His case offers hope to other patients and also illustrates our lack of understanding of the disease. Hawking is a famous physicist who has lived with amyotrophic lateral sclerosis since he was diagnosed in 1963 at the age of twenty-one. He has a very slowly progressing form of the disease 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 is gradually worsening. He's confined to a wheelchair and needs special equipment in order to communicate. He is still exploring theoretical physics, however, and is making some interesting proposals about the nature of the universe.

The Nervous System

ALS involves degeneration of motor neurons in both the brain and the spinal cord, which form the central nervous system or CNS.
ALS involves degeneration of motor neurons in both the brain and the spinal cord, which form the central nervous system or CNS. | Source

Finding a Cure for ALS

It's very hard to create a treatment for a disease 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 ALS, so there may well be multiple causes of the disease and different processes that lead to similar symptoms.

The only drug that extends life for ALS patients at the moment is riluzole (brand name Rilutek). This 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.

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 ALS. 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.

This is a section of a DNA molecule. DNA contains four nitrogenous bases - adenine, thymine, cytosine and guanine.
This is a section of a DNA molecule. DNA contains four nitrogenous bases - adenine, thymine, cytosine and guanine. | Source

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.

Gene Mutations

A protein-coding gene is a section of a DNA molecule that contains the instructions for making one 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.

DNA exists as a double helix.
DNA exists as a double helix. | Source

The SOD1 Protein and ALS

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.

A ribbon diagram representing the shape of a SOD1 molecule; the molecule is made of two polypeptides joined together. The arrows represent the direction of the polypeptide.
A ribbon diagram representing the shape of a SOD1 molecule; the molecule is made of two polypeptides joined together. The arrows represent the direction of the polypeptide. | Source

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.

A model of Cu-ATSM; white = hydrogen, black = carbon, blue = nitrogen, yellow = sulphur, orange = copper
A model of Cu-ATSM; white = hydrogen, black = carbon, blue = nitrogen, yellow = sulphur, orange = copper | Source

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.

A capillary in the brain, showing the tightly-packed endothelial cells
A capillary in the brain, showing the tightly-packed endothelial cells | Source

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. The researchers hope to start clinical trials in humans as soon as possible.

Secondly, the discovery most obviously applies to certain cases of familial ALS. There is evidence that SOD1 problems are involved in at least some people with sporadic ALS, however, so the new discovery may be useful for this type of ALS as well. 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 bring 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.

The Oregon State University researchers must demonstrate that the higher doses of Cu-ATSM needed to (potentially) treat ALS are safe before they can start clinical trials. If the clinical trials are successful, the copper compound will probably be offered to the general ALS population. 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. One of the researchers has posted an online letter to 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.

© 2016 Linda Crampton

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    • DDE profile image

      Devika Primić 16 months ago from Dubrovnik, Croatia

      I learned a lot of this disease from you. It is difficult to understand the cause. I watched the movie based on the true life of Stephen Hawking.

    • billybuc profile image

      Bill Holland 16 months ago from Olympia, WA

      My goodness, my friend, you outdid yourself with this treasure chest of information. I feel like I just sat in on a college course. :)

    • AliciaC profile image
      Author

      Linda Crampton 16 months ago from British Columbia, Canada

      Hi, Devika. I haven't seen that movie yet, but I want to. Thanks for the visit and comment.

    • AliciaC profile image
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      Linda Crampton 16 months ago from British Columbia, Canada

      Thank you very much, Bill. I appreciate your kindness!

    • RTalloni profile image

      RTalloni 16 months ago from the short journey

      So interesting. Thank you for sharing what you've learned about ALS.

    • AliciaC profile image
      Author

      Linda Crampton 16 months ago from British Columbia, Canada

      Thanks, RTalloni. The topic is important to me, so I like to investigate it.

    • poetryman6969 profile image

      poetryman6969 16 months ago

      It's good to see some progress is being made. Too bad we can't get warring nations to compete by seeing who can cure the most diseases.

    • AliciaC profile image
      Author

      Linda Crampton 16 months ago from British Columbia, Canada

      I love your idea, poetryman! That would be a wonderful situation. Thanks for the visit.

    • Vellur profile image

      Nithya Venkat 16 months ago from Dubai

      I hope the Oregon State University goes ahead with the research and finds a definitive cure for this disease. Valuable information here, thanks for sharing. Voted up.

    • AliciaC profile image
      Author

      Linda Crampton 16 months ago from British Columbia, Canada

      Thank you very much for the comment and the vote, Vellur. I hope that the discovery is useful and that it helps as many ALS patients as possible.

    • FlourishAnyway profile image

      FlourishAnyway 15 months ago from USA

      This was enlightening. Do you know if the copper deficiency is a nutritional deficiency and if so where we typically acquire trace elements normally? Wonderful hub!

    • AliciaC profile image
      Author

      Linda Crampton 15 months ago from British Columbia, Canada

      Thank you very much for the comment, Flourish. The copper deficiency appears to be a problem with respect to the mutated protein rather than an overall copper deficiency in the body. I'll be watching the news carefully for more information.

    • pinto2011 profile image

      Subhas 15 months ago from New Delhi, India

      Yes this ALS is a devastating disease but genius like Hawkins have still sailed through it even if there is no cure. The topic is really thoroughly described by you to be handy for someone who needs guidance.

    • AliciaC profile image
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      Linda Crampton 15 months ago from British Columbia, Canada

      Thanks for the visit and the comment, pinto2011. Stephen Hawking is certainly inspiring, although he has been severely affected by the disease. I wish other patients could live as long as him.

    • profile image

      Error antes 15 months ago

      Hello miss Alicia C. I was reading your hub about the problem with A. L. S. I am glad; scientist like yourself with a beautiful and dedicated mind are doing to discover the cure of diaseases. A. L. S. is a worry mind for those who feel threatened by all the symptoms of the illness. Practically the A. L. S. Take over people's life. Thank you for writing a well done hub full of hope for many people. Congratulations on your editor choice hub.

    • AliciaC profile image
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      Linda Crampton 15 months ago from British Columbia, Canada

      Thank you for the comment and the congratulations, Error antes. I'm a science teacher and writer but not a scientist, so I don't perform research into disease cures myself. I enjoy reading about the research carried out by science and medical researchers, though. They do important work.

    • Nell Rose profile image

      Nell Rose 15 months ago from England

      Hi Alicia, what a great amount of information. And something I knew little about, I knew about Stephen Hawking of course, but not that it was genetic as well as sporadic, interesting and sad disease, nell

    • AliciaC profile image
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      Linda Crampton 15 months ago from British Columbia, Canada

      Hi, Nell. Thanks for the visit. Yes, it's a very sad disease. What I also find sad is that my mother died of the disease many years ago and yet we still don't understand it and still can't cure it. I hope the new discovery leads to some significant developments.

    • manatita44 profile image

      manatita44 15 months ago from london

      Very informative and educational article. Yes, Professor Hawkins is amazing! However, I tend to relate all things to Spirituality, and perhaps God wanted him to manifest in a particular way. This makes him extremely significant, like say a Mandela, Luther King jnr or Gorbachev.

      There is a lot of excitement now about Alzheimers. Maybe there is some connection with the proteins. They have a drug, a neuro-statin,, they say, which seems to be able to halt the progress of the disease.

      The video with the water bath was quite charming at the end.

      Have you tried your hands at becoming a Health Practitioner? Perhaps you'll do well. Wonderful and meaningful Hub.

    • AliciaC profile image
      Author

      Linda Crampton 15 months ago from British Columbia, Canada

      Hi, Manatita. Thank you very much for the kind comment. I've heard about the new Alzheimer's drug. I read that it might prevent the disease from developing rather than treat the fully developed illness, but it's still a very exciting and hopeful discovery!

      I'm not in a situation where I can train as a health practitioner, but it's an interesting idea. I hope the week ahead is a good one for you, Manatita.

    • Faith Reaper profile image

      Faith Reaper 15 months ago from southern USA

      Linda, wow, this is certainly a comprehensive hub here on the devastating disease of ALS. I can't think of anyone else here on HP who I learn more from than you. I voted for you in the Hubbie Awards last year for Best Teacher, and will do so again. You certainly know your stuff and your research is stellar always.

      I'm sorry about your mother having to suffer with this disease. She would be proud of you.

      Blessings always

    • AliciaC profile image
      Author

      Linda Crampton 15 months ago from British Columbia, Canada

      Thank you so much for such a kind and lovely comment, Faith. I appreciate all that you have said a great deal, especially the reference to my mother.

      Blessings to you and your family.

    • CrisSp profile image

      CrisSp 15 months ago from Sky Is The Limit Adventure

      This disease is very interesting and one that is quite hard to understand at the same time. My friend's father sadly suffered from ALS and although he is now resting in peace, it is still good to know more about the subject. Thus, I am passing this hub to him.

      Congratulations on a well deserved Editor's Choice Award.

      Thank you.

    • AliciaC profile image
      Author

      Linda Crampton 15 months ago from British Columbia, Canada

      Thank you very much for the comment and for passing the hub to your friend, CrisSp. I appreciate your visit and congratulations. There are probably many people who are interested in the disease because they have lost a loved one to ALS. Once you see how it affects someone, it's hard not to empathize with other sufferers and to want a cure for the disease.

    • bdegiulio profile image

      Bill De Giulio 15 months ago from Massachusetts

      Wonderful job Linda. How exciting to see that progress is being made against this terrible disease. Thank you for the education. Have a wonderful weekend.

    • AliciaC profile image
      Author

      Linda Crampton 15 months ago from British Columbia, Canada

      Thank you very much, Bill. It is exciting news, although I'm concerned about the fact that it may only help a subset of ALS patients. I hope you have a wonderful weekend as well!

    • Mel Carriere profile image

      Mel Carriere 15 months ago from San Diego California

      My Momma always told me to fold my clothes carefully. I guess down at the most fundamental building blocks of life proper folding is essential, so it turns out Mom was right again. People like Stephen Hawking are why we have to cure these diseases. We don't know what treasures we are losing when anybody dies. Great work!

    • AliciaC profile image
      Author

      Linda Crampton 15 months ago from British Columbia, Canada

      Thank you for the comment, Mel. Your Momma's advice is interesting! I think that anyone's death is sad, no matter who they are and what they have accomplished. It's sad for the person, their relatives and their friends and can cause the world to lose valuable skills and abilities, as you say. It's a great shame.

    • truthfornow profile image

      truthfornow 15 months ago from New Orleans, LA

      ALS seems like such a debilitating disease. I am glad there is some hope for better treatments. Some of those who have it seem to die so young. Very interesting read.

    • AliciaC profile image
      Author

      Linda Crampton 15 months ago from British Columbia, Canada

      Thanks for the visit, truthfornow. Yes, ALS can certainly cut life short. It's a horrible disease. I hope patients are helped soon.

    • Larry Rankin profile image

      Larry Rankin 14 months ago from Oklahoma

      Always educational.

    • AliciaC profile image
      Author

      Linda Crampton 14 months ago from British Columbia, Canada

      Thanks for the comment, Larry.

    • vespawoolf profile image

      vespawoolf 8 months ago from Peru, South America

      I have a friend whose father suffers from ALS. After reading this article, I feel I understand a little more about the disease. I hope someday better treatments can be found to combat it.

    • AliciaC profile image
      Author

      Linda Crampton 8 months ago from British Columbia, Canada

      I sympathize with your friend and their father, vespawoolf. I hope that better treatments for the disease are found very soon.

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