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The idea of the ice bucket challenge is to temporary replicate the effects of ALS, involuntary muscle movements.
There are two types of ALS, sporadic and familial. Most cases of ALS are “sporadic,” meaning they are diagnosed with no known cause. Sporadic ALS is not heredity, affecting over ninety to ninety-five percentage of people who has been diagnosed with ALS. Approximately, 5,000 new sporadic cases are diagnosed annually.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost.
A team of researchers led by Robert H. Brown Jr., chair of neurology at the University of Massachusetts Medical School, discovered the first gene linked to familial ALS. The first gene that linked to familial ALS was a protein anti-oxidant known as “superoxide dismutase 1”, or SOD1. SOD1 is the genetic change in some inherited cases of ALS that alters enzymes within the cells. Despite the fact that only ten percent of ALS cases are familial, Dr. Brown began to research the genetic causes of familial ALS to hope that one day the research would provide an understanding into the sporadic form of ALS.
Researchers pursue the belief that SOD1 protein is associated with Sporadic ALS. This leads Daryl Bosco and his colleagues to conduct a research that showed that an antibody known to bind specifically to mutant SOD1, also binds to SOD1 modified by oxidation indicating that the oxidized SOD1 protein shared characteristics with the mutant SOD1 protein. Experiments showed that in four out of the nine samples from individuals with Sporadic ALS, recognized SOD1 protein in the spinal motor neurons. The SOD1 protein taken from three of these cases proved to be toxic to the function of motor neurons in an experimental model. This research shows that under certain conditions and absent a mutation in the gene, a normal SOD1 protein can have the same toxic characteristics that are found in familial ALS, where SOD1 gene is mutated. Although it is still unclear to how mutations in the SOD1 lead to motor neuron degeneration, there is increasing evidence that mutant SOD1 protein can become toxic, which also helps researchers find the presence of SOD1 protein in selected cases of Sporadic ALS. This research in 2010, helps leads to the research in 2013, where researchers identifies the suspected genetic mutation in Sporadic ALS.
As of May 2013, researchers at Stanford University School of Medicine have identified mutations in several genes that may be associated with the development of ALS. Several of the “suspected genes” are chromatin regulators. Chromatin regulators are cellular proteins that control how DNA is packed into the nucleus of a cell and how it is accessed when genes are expressed. Aaron Gitler, associate professor of genetics, and postdoctoral scholar Alessandra Chesi collaborated with researchers from Emory University and Johns Hopkins University to collect genetic samples from Sporadic ALS patients. The research compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequence of all the proteins in a cell. Mutations were only found in the Sporadic ALS patient’s exome, but not in their parents’. Using the exome sequencing approach, the researchers identifies twenty-five “de novo mutations” in the patients.
De novo mutations is an alteration in a gene that is present for the first time in one family member as a result of a mutation in a germ cell of one of the parents or in the fertilized egg itself. One of the five chromatin regulatory proteins, SS18L1, is strongly expressed in the brain and spinal cord, which affects the ability to form dendrites that are essential to nerve signaling. Gitler established that “in one Sporadic ALS case, the last nine amino acids of this protein are missing.” Establishing that these missing amino acids are important to the function of the protein, in SS18L1, neurons were unable to extend and grow new dendrites as normal neurons in response to stimuli. SS18L1 showed that the mutation carried by some patients is damaging to the protein and affects the ability of motor neurons to form dendrites. The research also showed that SS18L1 appears to physically interact with another protein known to be involved in cases of Familial ALS. Even though the researchers need more proof to prove how mutations in SS18L1 contribute to Sporadic ALS cases, they now have an idea of where to look in other patients. After this research, Chesi and Gitler are planning to sequence SS18L1 and other suspected genes in few thousand Sporadic ALS cases.
Scientists have known since 2010 that one of the suspected genes codes for for the protein “superoxide dismutase 1” or SOD1 is an enzyme that protects cells against oxidative damage by destroying free groups of atoms. Recently in 2014, researchers at Cornell University has uncovered a new insight into the causes of ALS, using a technique that illuminates subtle changes in individual proteins. Brian Crane, professor of chemistry and chemical biology at Cornell University, and his colleagues have provided strong evidence to support their hypothesis that SOD1 mutations cause ALS by destabilizing the SOD1 protein structure. Destabilizing the SOD1 protein structure, this leads to increased motion of the proteins that promotes their the ability to clump together, which causes the healthy cell to become toxic. Crane used a ESR spectroscopy, to finally see the distinctive differences between the properties of normal proteins and mutates ones because people who have studied mutations in SOD1, found the properties to be very similar. With the ESR spectroscopy, Crane said that the research showed the dynamics of the proteins were dramatically changed by mutation, showing a tendency to aggregate. Supporting the ESR spectroscopy data, Crane also used x-ray scattering to study the structural changes and the ability of the proteins to interact with each other. The researchers results from the x-ray scattering was that the levels of protein aggregation correlated with the severity of ALS symptoms. Crane has concluded with his findings that it’s possible Sporadic ALS to be linked to the toxicity of aggregation and not about the effects of the mutations in SOD1 activity.
Pete Frates, former Division 1 college athlete as the Captain of Boston College Baseball, has recently diagnosed ALS. Unlike Gehrig, Frates took it upon himself to help spread awareness about this “often misunderstood” and presently incurable disease. In March 2013, Frates had earned an audience at Food and Drug Administration to gain more attention and more action towards ALS, to find a cure. The following year, Frates’s friend, Rob Van Winkle, introduced him to the ice bucket challenge and Frates decided to ask others to do it for his charity and his cause, ALS. It started with Julian Edelman from New England Patriot doing the ice bucket challenge for Frates to raise awareness. Suddenly, athletes all over Boston started doing the ice bucket challenge. Then, athletes across the country started doing the ice bucket challenge. Teams, celebrities, families, everybody were all doing the challenge to help raise awareness and “#StrikeOutALS”. In less than a month, the challenge became a viral sensation and fundraising engine. As of August 29, 2014, the ALS Ice Bucket Challenge has raised over one hundred million. According to the ALS Association, since Pete Frates’s challenge, more than three million people have donated.
1903-1941
ALS became known in the United States when Lou Gehrig, a famous Yankee baseball player, was diagnosed with ALS in 1939. Lou Gehrig had sporadic ALS, which he died of two years later. ALS had soon became known as Lou Gehrig’s disease in honor of Lou Gehrig’s death. Since Lou Gehrig’s death, scientists in 1993 took a step towards answering the cause for ALS.
In 1869, French neurologist Jean-Marie Charcot had noted the first reports of the characteristics of ALS and explained how the central nervous system works. Charcot concluded that ALS weakens skeletal muscles, but is usually considered painless. He also found that many patients with ALS have muscle spasms, cramps, and atrophy.