ALS - Part 2 - Theories on ALS

Theories on ALS

  Excitotoxicity Theory

One theory of the disease mechanism for ALS is the ecitotoxicity of the motor neurons (Foran and
Trotti).  Excitotoxicity is defined as toxic actions by excitatory amino acids that result in cell
disease.  The amino acid, glutamate, is the foremost excitatory neurotransmitter in the Central Nervous
System.  Brain cells use glutamate as a neurotransmitter (communicator between neurons). 
When glutamate is released in excessive amounts, intercellular communications stop. The excess
glutamate at the neurons drives the neurons into hyperactivity and then to cellular degradation(Segala). (See appendix for a more detailed explanation of this process.)

  Glutamine

Glutamine is an amino acid.  Muscles in the body are made up of over 50% Glutamine.  However, in the
brain, glutamine is converted to glutamate for use by the neurons for communication (Blaylock).  When the brain finishes using the glutamate, the glial cells synthesize  the glutamate back into glutamine and it is stored for reuse.   Only if the glutamate accumulates does it become an excitotoxin for
neurons.  When glutamate arrives at the motor neuron receptor, calcium ions enter into the cell. 
If there are excessive levels of calcium ions coming in to the cell, damage to the neuron may occur
(McCarthy).

Magnesium deficiency may also play a role in ALS since the presence of enough magnesium may help to reduce the excess intracellular calcium. An accumulation of glutamate can occur when too much is ingested into the cell or too little is expelled.  Damage to the normal mechanisms by which glutamate is removed from the Central Nervous System may be the underlying cause for excess glutamate at the
neurons (McCarthy).

Excess glutamine accumulation has been associated with a worse prognosis in ALS(Blaylock).  High levels of glutamine in the brain increase free radicals and impair the mitochondria’s ability to produce energy (Blaylock).  The only drug which has been approved by the Food and Drug Administration (FDA) for the treatment of ALS works by reducing the amount of excess glutamate  absorbed by the cells (LEF Protocol for ALS).

Aspartame (found in many diet sodas) can act as an excitotoxin. Excitotoxins like glutamate and aspartate can cause a loss of brain synapses and connecting  fiber (Blaylock).  Dietary intake of glutamate (which includes MSG or Monosodium Glutamate) has been associated with increased risk of ALS (Segala). It is recommended that people with ALS avoid foods with high levels of glutamate (over 1 gram per 100 grams – or 1%). These foods include parmesan cheese, soy sauce, Roquefort cheese and many processed foods with added glutamates(Segala).  Ingredients that always include MSG  are: Autolyzed Yeast, Glutamate, Monopotassium Glutamate, Textured Protein, Yeast Nutrient, Calcium Caseinate, Glutamic Acid, Monosodium Glutamate, Yeast Extract, Gelatin, Hydrolyzed Protein, Sodium Caseinate, and Yeast Food. Note that MSG is comprised of 78 percent free glutamic acid  (Mercola, MSG: Is This Silent Killer Lurking in Your Kitchen Cabinets).

Excess glutamine accumulation has been associated with a worse prognosis in ALS(Blaylock).  High levels of glutamine in the brain increase free radicals and impair the mitochondria’s ability to produce energy (Blaylock).  The only drug which has been approved by the Food and Drug Administration (FDA) for the treatment of ALS works by reducing the amount of excess glutamate  absorbed by the cells (LEF Protocol for ALS).

  Mitochondrial Abnormality Theory

One of the theories put forward to explain the onset of ALS involves mitochondrial abnormality. These abnormalities have been identified in ALS patients (LEF Protocol for ALS).  Mitochondria are organelles in each cell that produce energy, maintain calcium  homeostasis, play a key role in apoptotic cell death and create reactive oxygen species (free radicals). The mitochondria’s main function is to provide energy
in the cells by producing adenosine triphosphate (ATP).

Homeostasis refers to the cell's ability to physiologically regulate its inner environment to ensure its stability in response to changes in its outside environment.  Mitochondria have their own membranes
inside of the cell membrane to maintain a microenvironment different from the cell they inhabit (Kidd). 
Mitochondria also have their own genome (set of chromosomes) that is separate from the cell’s genome.   The cell has multiple mitochondria which can divide and multiply and can fuse and separate with one another (Kidd). Additionally the mitochondria produce free electrons.  The mitochondria also process oxygen molecules as they produce energy, with byproducts of water (H2O) and free radicals of oxygen called reactive oxygen species (“ROS”) (Kidd).

The standard estimate is that an optimally functioning mitochondria converts up to 95% of oxygen into water and 5% or more is converted to ROS. Most ROS in the body is generated by the mitochondria, and the body has anti-oxidant defense enzymes to deal with these destructive free radicals. However, according to  Parris Kidd, the enzymes available are not 100% effective (Kidd). People can add antioxidants to their diet which helps to fill the gap.  However, some of the ROS are not destroyed and these damage the cell and/or the mitochondria.

The Free Radical-Mitochondria (FRM) theory of aging and the development of degenerative diseases “essentially assert that cumulative oxidative injuries to the mitochondria, triggered by endogenous metabolic processes and/or by exogenous oxidative influences, cause the mitochondria to progressively become less efficient.  As they become less efficient, the mitochondria produce less energy and a vicious cycle arises as more damage occurs in the mitochondria’s function and less energy becomes
available” (Kidd).

Damage from ROS also occurs to the antioxidant enzymes, the DNA, RNA, the cell-membranes, and other parts of the cell.  “Eventually the cell is either crippled, killed outright (necrosis), commits suicide (apoptosis), or loses growth control and becomes cancerous” (Kidd). The death of the motor neuron cell is what happens in the ALS disease process. As a person comes into contact with substances that have
oxidative potential, such as industrial chemicals, pollution, toxic food, this adds to the oxidant burden of the cells (Kidd). Parris Kidd asserts that the greater the amount of external oxidative stressors (toxic food, air and water), the more rapid the loss of function in the cells, and this is especially
evident in the brain.

Studies of mice modified to have the gene TDP-43, which is linked to both sporadic and familial ALS, show an abnormal form and structure of mitochondria.  Cells surrounding the motor neurons, the astrocytes and microglia, also show mitochondrial defects (Da Cruz).  However, Da Cruz states that not all ALS patients have consistently shown defects in their mitochondria.    Now researchers need to determine if mitochondrial defects cause ALS or are a result of the ALS disease  process.

Supplements that may protect mitochondria include CoQ10 and creatine (Segala). CoQ10 is used to regulate the oxidation of fats and sugars into energy (Segala).  Notably, this enzyme level decreases during normal aging. Creatine stabilizes the production as well as the transportation of energy within the cells (Segala).

  Viral Origin

There does not appear to be any current research into the viral theory of ALS origin. However, the Life Extension Foundation website refers to virus as a possible cause.  Dr. Stan Gross, a chiropractor and acupuncturist who has a special interest in patients with ALS, also believes virus may be a possible trigger.  And Dr. Sherry Rogers, a physician who specializes in environmental medicine, also indicates that a virus is a potential cause for ALS (S. A. Rogers, Detoxify or Die).

  Oxidative Stress or Free Radical Damage Theory

To explain the cause of sporadic ALS, some researchers point to free radicals.  Free radicals are molecules that have an unpaired electron that makes them very reactive with other molecules that contain oxygen. 

The free radicals cause oxidative damage to nerve cells and eventually destroy them (LEF Protocol for ALS).  Every cell generates toxic metabolites in the ordinary business of living.  Sometimes the free radicals are used to fight germs but an overproduction can result in cell damage and death.  The cell has defenses against the damage including the enzyme SOD-1, which is one of the genes implicated in causing the familial form of ALS (McCarthy).  Some researchers have shown that there are excessive levels of proteins damaged by free oxygen radicals inside the neurons of ALS sufferers.  The researchers believe either the neurons are generating too many free radicals or that the neuron is not able get rid of the ones it is producing (McCarthy).  When the SOD-1 gene is mutated or damaged, then it does not provide necessary protection to the neuron against free radicals.

  Immune Response Theory

Once a motor neuron is damaged, the immune response may be a factor in the development of ALS. 
The immune cells include microglial cells and astrocytes.  These can respond to an injured motor neuron and either clean up the damage or trigger a complete programmed cell death (“PCD”) (McCarthy).  It may be that the immune response in the ALS patient is greater than required by the impaired neurons and the response needs to be moderated.

  Enzymes, Proteins and Neurofilaments

A signature feature of ALS is the increase in neurofilaments (proteins) inside the motor neurons.  These neurofilaments are theorized to be responsible for the neuron’s shape and structure.  A study by Robert Brown and Daryl Bosco reported in the MDA/ALS Newsmagazine is corroborating the significance of the increase in neurofilaments (Wahl). This study found that the normal SOD-1 gene can produce SOD-1
proteins that after oxidization are abnormal and misfolded.  When oxidized, these proteins act similarly to the protein molecules that are made from the familial form of ALS. This finding points to a common mechanism between the familial version and the sporadic version (Wahl).  Once the misfolding occurs, the transport of substances along the nerve fibers is impaired, which is believed to play a role in the ALS disease process. 

There are enzymes within the Central Nervous System that regulate cellular processes.  Abnormal levels of these enzymes (called Protein Kinases) are found in ALS tissues after death.  This abnormal ratio may trigger the programmed cell death (McCarthy).

Some enzymes are used to clear away damaged proteins in the cell. These are proteasomes and
protein chaperones.  Their role in the pathogenesis of ALS is also being investigated by researchers
(McCarthy).

  Cell Transport, Aggregates, Neurotrophic Factors and Glia Cells

During initial states of motor neuron diseases like ALS, cell transport systems are disturbed in the motor neurons (Nordqvist). Cell transport systems are what bring nutrients into the cell and export waste products out of the cell.

Aggregates are unusual clumps of protein molecules that accumulate in the motor neurons of ALS patients.  This theory of ALS disease progression holds that aggregates upset motor neuron function
(Nordqvist).

Neurotrophic factors are a family of proteins that control the growth and survival of developing neurons as well as the maintenance and regeneration of mature neurons.  People with ALS do not produce neurotrophic factors correctly  (Nordqvist).  Neurotrophic factors can rescue motor neuron cells starting with the neuromuscular junctions all the way to the motoneuron cell body from apoptotic and excitotoxic death(Henriques, Pitzer and Schneider).  More trials with neurotrophic growth factors should be done since these have an excellent safety history and have a basis for being supportive to motor neurons (Henriques, Pitzer and Schneider).

Glial cells support neural cells by performing "housekeeper" functions such as clearing out debris and excess materials, insulating the neuron, and providing needed nutrients. There are several different types of glial cells such as astrocytes, microglia, and Schwann cells. It is estimated that for every neuron there are 10 to 50 glial cells in the brain (Cherry).  In some studies of ALS patients, the astrocytes have been found to not be functioning properly (Svendsen).

  Heavy Metal Theory

ALS tends to cluster in geographic regions like Guam and Japan.Environmental exposure has not been credibly proven as a cause of ALS. However,  implicated risk factors include smoking, pesticides, electromagnetic fields, and  heavy metals (Kamel, Umbach and  Stallone).

Support for the heavy metal and environmental agent theory comes from sources like Marco Vinceti’s paper.  In the paper, Selenium, especially in inorganic form and at low concentrations, was found to be a risk factor for ALS.  This paper discusses two epidemiologic studies from places with naturally
occurring selenosis and with high concentrations of selenium in the public tap water in addition to veterinary medicine observations and toxicological studies involving selenium. Some studies also point to people exposed to certain heavy metals such as mercury (LEF Protocol for ALS).

Another study suggested that ALS risk is elevated in construction workers and in precision metalworkers
(Fang, Quinlan and Ye).  This study correlated exposures to cutting, cooling, or lubricating oils
and chemicals such as aliphatic hydrocarbons (like methane, paraffin’s, ethylene, and acetylene), glycols, glycol ethers, and n-hexane with a higher risk of ALS, especially with nonsmokers (Fang, Quinlan and Ye).

In one interesting but small study, lead exposure as measured in blood and bone levels was shown to be associated with higher risk of ALS.  However, lead exposure did not shorten survival time of those diagnosed with ALS(Kamel, Umbach and Stallone). This study also referred to a recent study that found a cluster of ALS clients near an active lead smelter in Missouri. 

One of the factors making heavy metal exposure more dangerous is that heavy metals are not metabolized or broken down.   If not eliminated through feces, sweat or urine, the body accumulates and stores the heavy metals in tissues, organs and bone  (S. A. Rogers, Detoxify or Die). Organo-metallic forms of heavy metals can cross the cell membranes as well as the blood-brain barrier (Martin and Andonian).  When  there are heavy metals present, they can displace the appropriate metal species in the cell.

According to the article by Martin and Andonian, “heavy metals harm the body by tying up binding sites on cells, thus preventing essential minerals from getting into the cells.  In the human system, bivalent metals are engaged in a continuous fight for the site against one another; the result is displacement of the element of lesser atomic mass by another of a heavier atomic mass.  Heavy metals grab the biological spaces that would have been filled with necessary minerals that are lighter in mass.  As an example, mercury and cadmium, which are toxic heavy metals, are in the same group in the periodic table of elements as zinc, which is a beneficial mineral.  Mercury and cadmium, being heavier than zinc, can prevent zinc from being utilized and thus result in zinc deficiency…If [the] ratio of protective nutritional metal to toxic heavy metal falls below an ideal level, then the heavy metal could be interfering with the function of the protective metal, even if heavy metal is not in a toxic reference range.”

This indicates that measuring for heavy metal levels is not sufficient.  If the beneficial minerals are too low compared to the availability of the heavier metals, then the heavy metals will be utilized in building the body’s enzymes.  Heavy metals produce huge numbers of free radicals and thereby help to destroy nervous tissue.

In 2001, the Defense and Veterans Affairs departments issued a joint announcement that veterans of the first Persian Gulf War were nearly twice as likely as other soldiers to suffer from ALS (Stolberg). Veterans with“Gulf War Syndrome” suffer from ailments that some believe to stem from chemical exposure, stress or “prophylactic medicines” given to soldiers (Stolberg). “Prophylactic medicines” include the vaccines given to soldiers, some of which contained aluminum hydroxide. Aluminum hydroxide is linked to symptoms  associated with ALS (Mercola, Mercury isn't the Only Toxic Item in Vaccines).  This compound is used in vaccines to stimulate immune  response.

The anthrax vaccine that was developed for use in the first gulf war was tested on mice. Thirty five percent of the cells controlling movement in those mice were destroyed (Mercola, Mercury isn't the Only Toxic Item in Vaccines).

  Head Trauma

Repetitive head trauma has also been linked to ALS (Daniloff).  The researchers at Boston University examined the brains and spinal cords of deceased athletes, some of whom had been previously diagnosed with ALS.  These athletes had an abnormal protein, TDP-43, in a unique pattern and distribution as well as deposits of an abnormal form of tau protein.  Abnormal tau deposits are not found in ALS cases but are found in people that have been diagnosed with CTEM (chronic traumatic encephalopathy), formerly known as “punch drunk syndrome.”

One of the risk factors for ALS is head trauma which may result from being a collision athlete such as a boxer or football player or being a military veteran with a history of head injury (Daniloff).  It is
interesting that head trauma can initiate neurodegeneration.  The symptoms of ALS patients and of CTEM patients are very similar although CTEM patients typically show behavioral changes and cognitive decline, while, according to Daniloff, ALS sufferers retain their faculties.  However, many other articles state that a significant number of ALS patients do experience cognitive difficulties (Tsuji-Akimoto, Hamada and Yabe).  Therefore, differentiation between CTEM patients and ALS patients cannot depend on using cognitive decline for  diagnosis.

Other researchers are disputing the finding that ALS could be caused by head trauma (Scientific Validation Lacking in Reports Claiming ALS Caused By Head Trauma).   These experts are claiming that the three athletes examined must have had both the CTEM disease as well as ALS. In support of the Daniloff study, past physical trauma makes the brain susceptible to becoming a storage site for heavy metals (Klinghardt).  Given this susceptibility as well as that collision sports is a risk factor of ALS, this could lend support to the theory of heavy metal exposure leading to ALS as well as CTEM when physical trauma is present.

This paper is in honor of Warren Schaeffer, an exceptional
person, adventurous being and a first-class gentleman.