Cobbers on the Brain

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. According to U.S. population studies, approximately 6,000 people in the U.S are diagnosed with ALS each year, with an estimated 20,000 Americans living with the disease at any given time. The average survival time is three years and currently there is no known cure. However, through millions of dollars of research, scientists have hypothesized a variety of explanations for factors that might increase the risk of ALS.
The Risk Factors
Though it is known that ALS can affect anyone, occurring throughout the world with no racial, ethnic, or socioeconomic boundaries, research has shown that it occurs in greater percentages as men and women grow older, and it is significantly more common in men than women. Additionally, military veterans are approximately twice as likely to develop ALS and many athletes are known to be diagnosed with ALS later in life. There have been several research studies investigating additional risk factors that may contribute to ALS, with the argument being that environmental factors in conjunction with genetic susceptibility cause the disease. Here is a list of the most common risk factors discussed today:

• BMAA (Beta-methylamino-I-amine)
• Toxins: metals, solvents, radiation
• Exercise
• Smoking

The Link
As mentioned previously, it has been found that the link between military veterans and ALS is significantly high, in specific military veterans from the Gulf War. Some scientists believe that for veterans born with a genetic flaw that predisposes them to ALS, the military’s exhausting physical demand perhaps triggers the disease to erupt later. Others hypothesize that the vaccinations military veterans had to receive before deployment could play a role in the onset of the disease. However, a more a more popular link, one that was studied by the University of Cincinnati and  Duke, Durham Veterans Affairs Medical Center, controlled for neural toxins and found that the veterans stationed at the munitions dump in Khamisiyah, Iraq during the Gulf War experienced a heightened risk of disease. During the demolition of this dump, a low level of nerve agent and smoke from the oil well fires were released consistently.
Consistent with this hypothesis, on the small island of Guam, there is a large munitions storage area. Rates of ALS are similarly high in people living in Guam, just as they are in military veterans stationed around munitions sites during the Gulf War.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Furthermore, it results in the degeneration of upper and lower motor neurons responsible for voluntary movements and muscle control, resulting in progressive loss of speech, atrophy, fasciculations, and eventually respiratory failure when diaphragm and chest muscles fail. While about 10 percent of those with ALS survive for 10 or more years, most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of symptoms. There are two different types of ALS, sporadic and familial. Sporadic which is the most common form of the disease in the U.S., is 90 – 95 percent of all cases. It may affect anyone, anywhere. Familial ALS (FALS) accounts for 5 to 10 percent of all cases in the U.S. At present, there is no cure for ALS and most treatments are designed to relieve symptoms and improve the quality of life for individuals with the disorder. That being said, how far should treatment go given the invariably fatal nature of this disorder and the associated degree of paralysis?
Given a choice, most people would prefer to prolong their lives for as long as humanly possible, largely in the hope of a medical miracle bringing them back from the brink of death, possibly to their former self or a similar rendition of the same. In the case of ALS, death is slow but certain, and in its late stages, patients experience total paralysis, including that of chest wall and diaphragm muscles (See diagram below of atrophied muscle in ALS). At this point, one may argue that there is still some sentimental value to the physical presence of one’s loved one regardless of their physical state. In my view, furthering the life of a late stage ALS patient on a long term basis is an impractical and unsustainable route for all parties involved. In the case of few patients that can afford the medical care, only the health care institutions benefit from the situation while friends and family incur extremely steep financial costs. In the larger share of patients who cannot afford being placed on a ventilator and being continually hospitalized, their bill becomes the responsibility of the state and health care infrastructure as a whole, an all round lose-lose scenario for all parties involved.
In precis, while my position may sound insensitive to some, or shallow on the account that I write from a third party viewpoint, it is imperative for this discussion to be initiated and sustained. Also, families in this predicament ought to be earnestly well informed about the contours of the journey they are on through conversing with social workers and the health care professionals serving their loved ones. While civilization has made huge leaps and bounds to prolong life through the ingenuity of medical researchers in disciplines such as surgical, pharmaceutical, and nutrition research, it is also incumbent upon ourselves to perform cost benefit analyses such that we avoid engaging in futile cycles in which we continue to expend financial and other resources to sustain life at all costs, even though the nature and quality of life may deteriorate to less than a shadow of its former glory.
 
 
Below is a diagram of muscular differences between normal and ALS diseased muscle.

 
 

Last week, my neurochemistry class studied the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Throughout the week, we dove deeply into the neurochemical mechanisms behind ALS, namely the interacting roles that reactive oxygen species and ineffective RNA metabolism play in the development of the disease.
According to current research, chronic oxidative stress (and the resulting reactive oxygen species produced by mitochondria) can lead to the aggregation of RNA binding proteins like FUS and TDP43 in the cytoplasm. Aggregation of these proteins can eventually lead to their loss of function, which can have dangerous effects due to the concomitant sequestration of chaperone proteins. With the loss of chaperone proteins, the body struggles to properly fold proteins that aid in responding to oxidative stress.
Interestingly, the relationship appears to be reciprocal, as RNA dysmetabolism can also cause oxidative stress and accompanying mitochondrial damage. In this proposal, when the FUS and TDP43 proteins are mutated or sequestered in the cytoplasm, the cell loses key anti-oxidative stress pathways. In the case of TDP43 loss of function, the cell experiences gene transcription from an activated family of FOXO transcription factors that leads to mitochondrial damage.
And while the science was captivating and essential to our understanding of ALS, when it came to our end of the week debriefing, science didn’t carry the conversation. Instead, the ethical considerations associated with end of life care in ALS took center stage.
Reflecting now, I think we arrived at this topic from our discussions on the lack of treatments for ALS. To our knowledge, there is just one well-accepted drug, called Rilutek, that slows the disease progression in some people. The lack of options for treating ALS amazed me and filled me with sadness. It ultimately drove home the inevitability for many people stricken with ALS of being trapped inside one’s own body. This happens because of a disconnect between mind and body where mind isn’t the issue. Instead, the motor neurons in the spinal cord are destroyed whilst sparing the neurons in the brain.
To our class, this maintenance of mental capacity throughout the disease raised important questions about a patient’s wishes at the end of life. Since they are mentally capable, should a suffering ALS patient have the right to end his or her life through physician assisted suicide? One student even held the opinion that after a patient dropped below a certain quality of life, their insurance should increase as to cover the exorbitant costs of maintaining someone’s life.
In the end, what we were all struggling to decide was the best option for both the patient and family. ALS certainly presents a unique situation because unlike other debilitating diseases, these patients retain their mind and personality and even take pleasure from seeing their loved ones and communicating with them. Yet, when the disease reaches such an advanced stage where speech is impossible, breathing is difficult, and someone’s individuality is gone, who benefits then? I agreed with many of my classmates that if they or a family member were in this position, they would want a quick and peaceful ending. However, I had second thoughts this past weekend after reading about technologies that enable late-stage ALS patients to communicate.
The study was published in the Journal of Neural Engineering and involved research into a new brain-computer interface (BCI) technology. The researchers built off of the fact that current BCI technology isn’t effective for ALS because the current systems depend on brain processes that are impaired in ALS. That’s why the new technology targeted a different area of the brain called the precuneus, which is located in the parietal cortex. This brain area is associated with consciousness and is not affected in patients with ALS. The study was small and only involved two patients, but the results were exciting. The researchers trained the two patients to self-regulate two types of brain waves, theta and gamma, in the precuneus. With their ability to activate either brain wave on command, the patients could answer questions and participate in simple conversation.
Technologies like this truly demonstrate the need for science and could one-day help ALS patients maintain relationships with their children and grandchildren. Yet, part of me is still saddened that previously vibrant individuals could be confined to the equivalent of a yes or no answer.
Despite the 40 minutes of discussion my class spent on the topic, I’m still on the fence. I think this mental struggle on my part is a testament to the difficulty of the problem but demonstrates the importance and need for these discussions to take place. With no signs of a game-changing therapeutic approach to ALS coming soon, we need to thoroughly consider what good we are doing by extending the lives of ALS patients indefinitely. Who knows, we may realize that our healthy intentions have taken us in the wrong direction.

Many of the neurodegenerative diseases have new information coming out on it. Amyotrophic Lateral Sclerosis (ALS) is one of the diseases that people are aware due to its relation with Stephen Hawking, but are not familiar with the symptoms or cause of ALS.  ALS symptoms can vary between people, but it is a gradual, painless onset of muscle weakness because it affects the motor neurons within the spinal cord.  Initial symptoms can include tripping, dropping items, fatigue, and slurred speech.
Genetic mutations along with environmental factors can be seen as the cause of ALS. The cause of ALS can be sporadic (non-familial) which accounts for 90% of ALS patients or familial which accounts for 5-10% of ALS patients. A common theory is that sporadic mutation when paired with an environmental factor, can cause ALS. Of the familial ALS patients, around 60% have a genetic mutation. Most frequently heard of is the SOD1 mutation which has caught a lot of attention. However, there are other mutations that individuals should be aware of that have been linked to ALS such as FUS, TDP43, and C9orf72.
SOD1
The SOD1 mutation is responsible for 15-20% of familial cases in the world. SOD1 is an enzyme typically localized to the cytoplasm, nucleus, lysosomes, and mitochondria. It is involved in the body by attaching to copper or zinc and breaking down toxic superoxide radicals. It then forms ribonucleoprotein complexes in the brain and spinal cord. Within familial ALS, around 200 mutations in the gene have been linked. Most of the mutations result in an amino acid change within the protein of the enzyme. Mutations cause SOD1 aggregates to form in the cytoplasm and ribonucleoprotein complexes are not able to form which reduces the half-life.
FUS
The FUS mutation is responsible for around 5% of cases. The FUS protein regulates transcription by binding to DNA, prevents genetic damage by repairing DNA mistakes, and is involved in alternative splicing, processing, and transporting of mRNA to other cell structures to become a mature protein. Mutations involving this gene are found in ALS, Ewing sarcoma, and cancers (AML). Within ALS, the FUS gene can have around 85 mutations occur.  The mutations usually affect building blocks in FUS protein, DNA binding, mRNA processing and transporting. This results in FUS protein and mRNA being trapped within the cell creating aggregates and stress granules. The picture below shows how the mutations can affect RNA metabolism.

TDP43
The TDP43, also referred to as TARDBP, mutation is responsible for around 5% of cases. TDP43 is a RNA-binding protein and found in very small concentrations in the cytoplasm of healthy individuals. Some of the functions of this protein are similar to the FUS protein above, including transcription and splicing of mRNA. However, TDP43 aggregates are found in the brain tissue of post-mortem ALS patients which lead to it being studied for ALS.  Oxidative stress and mutations lead to more of this protein being moved into the cytoplasm and causing stress granules. There are nearly 30 mutations, the majority occurring in the C-terminal (shown in the picture below), that have been connected to ALS. The picture above shows how the mutations can affect RNA metabolism.

C9orf72
The C90orf72 mutation is responsible for 30-40% of familial cases in the US and Europe. C9orf71 is a protein found in neurons of the cerebral cortex and motor neurons of the brain and spinal cord. It is thought to play a role in the production and transportation of RNA and production of proteins. ALS occurs when a segment of the gene is largely repeated. It is not known if the repeat causes abnormal function.