The recent ALS awareness movement has been making a huge splash all over the country. While the “ice bucket challenge” has gone viral, awareness of the actual neurological disorder has not necessarily kept pace. Here we offer a brief overview of what is known about this mysterious illness.
Amyotrophic lateral sclerosis, or ALS, is a fatal neurodegenerative disorder which is characterized by the progressive deterioration of motor neurons – the neurons that help us control movement. Early symptoms of the disease include muscle atrophy, chronic cramping, slurred speech, and lopsided motility. Often within 2 years of diagnosis, most motor function diminishes and ALS patients die from respiratory complications.
Why respiratory failure? To understand why, we need to dive into the biology of motor neurons.
Movements that allow you to do things, such as pick up a cellphone, walk up a set of stairs, or take in a deep breath of air, are controlled by special nerve cells called motor neurons. These neurons link the motor cortex (a region of the brain which can initiate motility) to muscle fibers throughout the body, via the spinal cord.
ALS disrupts the ‘chit chat’ between the brain and muscles by destroying the motor neurons. Over time the severed contact greatly weakens the muscles and leaves the individual virtually paralyzed. Strangely, communication between almost all other neurons are preserved, leaving ALS patients with normal sensory ability (5 senses), cognitive aptitude, eye movement, and continence.
When we breathe, our neurons stimulate the diaphragm to contract and the intercostal muscles to extend; this thoracic expansion creates a cavity which is filled by the surrounding oxygen. Once ALS begins to break down the ability and control those muscles, even the simple act of clearing one’s throat becomes difficult. Without the ability to cough or effectively breathe, infection and suffocation inevitably follow. [share_this_post]
Only about 10% of ALS cases are linked by heredity – the majority of cases occur spontaneously. While some theories attribute spontaneous ALS to sports trauma, electrical injury, or even pesticide exposure, none have been supported by substantial evidence. What we do understand about the disease stems from the diverse mutations that have been found in ALS patients.
One of the most common genetic mutations is in the gene SOD1, which codes for superoxide dismutase 1. This enzyme normally reduces free radicals in the cell.
Scientists think that two downstream effects could be linked to SOD1 mutations: First, the increase in free radicals could disrupt the processing of vesicles at the synaptic junctions of motor neurons. This processing is a fundamental cellular mechanism for neuronal communication. The second effect may be that the mis-regulation of Copper and Zinc binding (two cofactors of SOD1) could cause the accumulation of plaques similar to those found in Alzheimer’s and Parkinson’s.
More recently, mutations in TARDBP, FUS, and other proteins that bind cellular messages (called mRNA) have been discovered in ALS patients. The role of mRNA processing in neurons is not well understood, but insights into how these binding proteins work and what messages they target will surely offer a broader picture of ALS mechanics.
In another breakthrough insight, scientists earlier this year discovered that a mutation known as C9ORF72, which is a hexanucelotide repeat, was present in 40% of familial ALS cases and 7% of sporadic cases.
This mutation does not directly affect any piece of the cell’s machinery; instead, regions of repetitive DNA affect the stability of hereditary material. If we think about the DNA as a book of hereditary information, a good analogy would be to think of C9ORF72 as a crack in the book’s binding.
Beyond these well-mapped mutations, the best characterized complication of ALS is the abnormal processing of glutamate (Often known as MSG). Glutamate is the main neurotransmitter found in motor neurons which also plays a crucial role in balancing the amount of calcium ions at the synapse. Any mass alteration in the amount of calcium or glutamate in the synapse can be toxic and result in the death of the neuron.
Given the number of recent advances in understanding ALS, it is unfortunate that so few drugs are available for the disease.
Riluzole is the only current pharmaceutical on the market for ALS. Although its function is still not fully understood, it has been shown to reduce glutamate accumulation and neuron death. Riluzole is still far from a miracle drug as it only extends life-span by a few months. Such a short period of efficacy is typical of a drug that relieves symptoms rather than causes of a disease.
Despite progress in our understanding of the disease, it is extremely unlikely that a cure for ALS will emerge in the near future. The broad spectrum of disparate mutations associated with the disorder have only intensified the diagnostic and pharmacological challenge. Yet, patterns are beginning to emerge, and the continued support for basic ALS research will surely offer clever new ideas to combat this enigmatic illness.
Image credit: Spinning disk confocal microscope image of Zebrafish Neurons highlighted with GFP (credit Kenric Hoegler)