Amyotrophic lateral sclerosis
I was recently challenged to participate in the latest viral social behavior: the ice bucket challenge. The activity raises awareness for Amyotrophic lateral sclerosis, now more commonly known as ALS. I have decided to respond to the challenge with this blog post rather than pouring water over my head, since I’ve come to realize that watching over twenty ice challenge videos has taught me next to nothing about the disease!
ALS is both the most common and most aggressive type of adult motor neuron degeneration. The death of upper motor neurons in the motor cortex and lower motor neurons in the brainstem and ventral horn of the spinal cord result in a progressive loss of muscle control. This progression is characterized by stiffness, overactive reflexes, muscle twitching, muscle atrophy, and finally full paralysis. Approximately 15% of patients also suffer from cognitive and behavioral problems known as frontotemporal dementia due to the death of neurons in the prefrontal and temporal cortex in the brain[1,5].
Finally, it is a heterogeneous disease: the age, site of onset, rate of progression, and the presence and degree of cognitive dysfunction can vary widely between patients. The disease is fatal within 3-5 years of onset.
The majority of ALS cases (about 90%) are sporadic – there is no family history of the disease. The minority of cases that are familial, or related to the family’s genetic history, are similar in both course and mechanism to the sporadic form. While mutations in over 10 different genes are recognized to cause the familial version, the exact cause of ALS remains elusive.
Nervous system review
Despite not knowing the precise cause, a good deal of ground has been covered regarding the pathogenesis of the disease. To best understand what happens during ALS, we need to have a basic understanding of the relevant parts of the nervous system.
Our nervous system is like the command center of our body. We use it to think, initiate muscle movement, detect and interpret the world around us, and regulate our body processes. Our nervous system is split into two categories: the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of neurons that make up the brain and spinal cord. The PNS is made up of sensory receptors, sensory neurons, and motor neurons.
A neuron is a funky looking cell that would look at home in a portrait of possible alien species. On one end we have the soma, a bulge containing the nucleus (the DNA) and most protein synthesis. Dendrites sprout from the soma like tree branches. These branches match up with and thereby receive signals from axon terminals (see below) of other neurons. At the other end of the soma, the neuron has a long, thin projection called the axon, which is coated with lumps of an electric insulating material to form myelin sheaths. Myelin is necessary to allow the signal to be passed rapidly down the axon, making the process nearly instantaneous. At the far end of the axon, we have another collection of branching tendrils known as axon terminals. These meet up with muscles or other neurons at a synapse in order to transmit a chemical signal or message.
The signal carried through neurons is called an action potential. We often hear the term “electrical” associated with neuron communication. This is because the signal is actually a change in electric charge in these cells. Ions, small charged molecules, are collected in neurons so that they have a higher concentration of negative ions inside. A neuron receives a signal on its dendrites from another neuron in the form of a chemical that causes ion channels to open. Because the cell is negatively charged inside, positive ions (sodium and potassium) flood in. This wave of positive charge, the action potential, moves down the axon and triggers the release of chemicals in the axon terminals. These chemicals travel across the synapse to another neuron or muscle, thus passing the signal onward.
Motor neurons are neurons that pass a signal onto a muscle, causing it to contract or relax. The axon terminals of motor neurons meet the muscle at a synapse called the neuromuscular junction. These neurons are the cells that die in patients with ALS.
Microglia have been recently implicated in the disease process of ALS[3,6]. These cells are a type of glial cell present in the brain and spinal cord. They are the primary form of immune defense for these areas. They are phagocytic cells (they “eat” debris), and consume and break down garbage such as damaged neurons and pathogens. They can release cytotoxic (toxic to cells) substances to help break down infected or damaged neurons and pathogens, which will come into play in ALS. They also communicate with other cells in order to organize cell defenses against pathogens and trigger inflammatory responses.
While these cells may have a protective effect in early stages of the disease, they become impaired and accelerate the progression of ALS during later stages. A mutation in the genes for this cell has been discovered to be at least partially responsible, as deletion of this mutated gene in mice models of ALS increases their survival. During the disease, microglia switch into an activated phase. In this active state, their size, shape, and actions change. They no longer secrete the chemicals used to keep neurons healthy and prevent inflammation. They trigger inflammatory responses in the spinal cord and cortex and release cytotoxic factors as well as reactive oxygen species[1,5]. All of these processes damage neurons. Additionally, they release chemicals that make healthy microglia less effective.
Astrocytes are also support cells for neurons. They provide nutrients, metabolic precursors, trophic factors, and regulate neuron homeostasis. Similarly to microglia, they lose their beneficial properties and switch into an activated phase in patients with ALS. The amount of astrocytes activated increases as the disease progresses. When activated, they release cytotoxic factors and reactive oxygen and nitrogen. They are unable to protect neurons from excitotoxicity: neurons are stimulated excessively, causing the cells to be flooded with positive calcium ions that damage cell components.
Oligodendrocytes are glial cells that create the myelin sheaths on neuron axons and also release lactate for neurons, which use it for cellular metabolism (to produce usable energy). These cells become dysfunctional in ALS, failing to release enough lactate for neurons and to successfully myelinate the axons, thereby causing cell death.
Neurotrophic Support Failure
Trophic factors are proteins essential for neuronal functioning, repair, and maintenance. As you can see from the loss of function in the aforementioned cells—all of which release trophic factors—there is a loss of trophic support for neurons. This leads to damage which is unable to be repaired, leading to a loss of neuronal function and subsequent cell death.
Mitochondria are the “powerhouses” of cells; organelles that produce energy molecules (ATP) that cells require for almost all of their processes. In ALS, mitochondria in neurons have been found to be damaged prior to the cell’s degeneration. While we do not know exactly why this is, any damage to or loss of mitochondrial function can influence the homeostasis of the cell and apoptosis (programmed cell death).
Impaired Axonal Transport
As described above, neurons have an extended section called the axon. These can be really, really long: As in, over 10,000 times the length of the soma. We have nerves whose axons run from the base of our spinal cord to our big toes! Consequently, we need to have a very efficient transportation mechanism to carry proteins, organelles, and anything else the cell needs to move from one end to the other. Cells achieve this via a network of microtubules that run the entire length of cells. These long ropes of protein form what we can think of as a cellular highway. Motor proteins use these highways to carry cargo around the cell in a herculean effort that requires quite a bit of the ATP made in mitochondria. Mutations have been found in a subunit of a protein, dynactin 1, whose purpose is to stabilize the binding of cargo to dynein, a motor protein.
Motor Neuron Death
All of these mechanisms contribute to neurodegeneration: the process of motor damage, loss of function, and death. The pathology in neurons has been found to begin in the synaptic area (axon terminals) and work backwards into the soma and dendrites. This has been called the Dying Back Hypothesis. At the beginning of the disease, the death of axon terminals and neurons can be compensated for by neurons growing new axons to innervate muscles. Unfortunately, as the disease progresses, for the rate of motor neuron death exceeds the ability of remaining healthy cells to compensate for their loss.
Impact on Muscles and Cause of Death
Damaged motor neurons are unable to properly signal muscles to contract. As the neurons lose function they may misfire, telling muscles to contract more frequently or involuntarily (twitching). Eventually, when the motor neurons die, there is no pathway for the signals to reach muscles and they can no longer be told to contract or relax; they become paralyzed. Once the paralysis reaches the muscles needed to breathe, the disease becomes fatal. Patients die of respiratory failure.
There is only one approved treatment for ALS: a drug called Riluzole that was approved in 1995. This drug can increase a patient’s lifespan by 2-3 months. There is no cure, although research into understanding the mechanisms of the disease will help provide targets for treatments. Cell replacement therapy is one prospective treatment in which stem cells isolated from bone marrow may be used to restore the healthy state of motor neurons and glial cells. Therapies targeting disrupted cell signaling mechanisms and restoring the activated cells to their healthy, inactive phase are other possibilities. Hopefully, the money raised through endeavors like the Ice Bucket Challenge can help fund progress toward a definitive cure!
 Brites, D and Vaz, A. “Microglia centered pathogenesis in ALS: insights in cell interconnectivity.” Frontiers in Cellular Neuroscience. 2014.
 Cunha, C. “Exploring motor neuron degeneration in ALS prevention by glycoursodeoxycholid acid and signaling to microglia.” 2012. Master’s thesis, Universidad de Nova de Lisboa.
 Dijab, P et al. “In vivo imaging reveals rapid morphological reactions of astrocytes towards focal lesions in an ALS mouse model.” Neuroscience Letters. 2-11/ 497.
 Pollari, E et al. “The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis.” Frontiers in Cellular Neuroscience.” 2014.
 Poppe, L et al. “Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS).” Experimental Neurology. 2014.
 Weydt, P et al. “Increased cyto-toxic potential of microglia from ALS-transgenic mice.” Glia. 2004. 48.