Research Paper on Amyotrophic Lateral Sclerosis

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that involves degeneration of upper motor neurons and lower motor neurons (UMN and LMN). The UMN is part of the motor cortex while the LMN extend through the spinal cord and brainstem, which trigger the skeletal muscle (Redler & Dokholyan, 2012, p. 215). The neurodegeneration can start from any part of the body and then continues until full paralysis is reached and eventually death. Life expectancy for ALS is generally from 3-5 years. ALS was initially discovered over 140 years ago by French neurologist Jean-Martin Charcot in 1869 when he was observing and connecting lesions in the gray and white matter with the progressive paralytic syndrome. However ALS was not a very well-known disease until Louh Gehrig, a famous baseball player was diagnosed with it in June 1939. His disease spread so quickly that he became paralyzed and died two years later in 1941. As of today, over six thousand people in the U.S. are diagnosed with ALS (Petrucelli, L., & Gitler, A. D. 2017, p. 46-51). According to Arizona State University, ALS is most common in people between the ages 40-60 years but younger, and older people may get it as well. As of today, there are not any real cures for ALS only treatments that help slow the progression of ALS.

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Molecular Biology of ALS

According to the ALS Association, the word "Amyotrophic" means "no muscle nourishment." When the motor neurons in the body begin to degenerate, they begin to lose the ability to send signals to the muscles until the brain no longer has control over muscle movement and muscles begin to wither away or atrophy. The areas of a person's spinal cord where muscles are controlled are known as "lateral." The term "sclerosis" refers to the hardening or scarring of the muscles. As stated earlier, neurodegeneration can begin in any part of the body, and it will spread throughout the body until all voluntary muscle movement is lost. This includes the ability to walk, movement of arms, swallowing, and talking. The muscles that are not affected by ALS are the eye muscles and urinary sphincters (Pasinelli and Brown, 2006, p. 1). Respiratory failure or loss of the ability to breath is the cause of death. The majority of ALS cases are sporadic meaning random, only 10% of cases are familial meaning passed down through the family.

Research has identified protein aggregation as a pathological hallmark in neurodegenerative disorders. A significant number of ALS cases are characterized by the abnormal accumulation of insoluble proteins in the cytoplasm of degenerating motor neurons (Liscic & Breljack, 2011). The abnormal protein is ubiquitinated, and the ubiquitin immunoreactive NCIs are located in the lower motor neurons. TDP-43, which is a 414 amino acid, is abnormally accumulated from the nucleus of neurons and glial cells. The TDP-43 is ubiquitinated and accumulated as abnormal C-terminally truncated form of 25 kDa (Liscic & Breljack, 2011).

The prominent roles of SOD1 and C9orf72 genes explain the genetic history of ALS. The discovery of SOD1 offered the platform to study the molecular basis and mechanism of ALS. SOD1 is a ubiquitous cytosolic enzyme that functions to dismutate the superoxide radical (O.2) to a less oxidizing species (H2O2) via a bound Cu2+ ion (Redler & Dokholyan, 2012). SOD1 develops independent mutants that kill motor neurons. Research on how the mutants grow and kill the motor neurons has not been concluded, but evidence indicates that misfold and aggregate are the primary causes of mutant genes of SOD1. Large-scale aggregates of SOD1 are toxic, and their insoluble inclusion bodies appear in the brain stem and spinal cord and accumulate progressively in the terminal stages. The non-native forms of misfolded SOD1 are present from birth and are located in specific motor neurons. The misfolded SOD1 become toxic and kill motor neurons when cells fail to function appropriately.

Etiology of ALS

According to Passilini and Brown (2006), five gene defects have been found to cause ALS. These proteins are cytosolic Cu/Zn superoxide dismutase (SOD1), alsin, senataxin (SETX), synaptobrevin/VAMP (vesicle-associated membrane protein)-associated protein B (VAPB), and dynactin. Loci have been associated with ALS (on chromosome 15, 16, 18, 20) and frontotemporal dementia ALS (ALS-FTD) as well.

Superoxide dismutase (SOD1) is a cytosolic protein consisting of 153 amino acids that function as a homodimer (Pasinelli and Brown, 2006, p. 710). Through the cyclical reduction of oxidation (dismutation) of copper, SOD1 converts the superoxide anion to hydrogen peroxide. Approximately 20-25% of familial ALS (FALS) cases originate from the SOD1 mutations. This protein only accounts for 0.1-0.2% in the CNS. Over 125 mutations have been found spanning through SOD1. One hundred and forty-three of these mutations cause disease while six silent and five intronic variants do not (Pasinelli and Brown, 2006, p. 711).

The mutation in the FUS gene, which is located in chromosome 16 has also been found to cause ALS. The FUS protein belongs to the family of RNA-binding proteins, which function to regulate gene expression, maintenance of genomic integrity and mRNA/microRNA processing (Naganska & Matyja, 2011). The FUS pathology has been identified in sporadic ALS and familial ALS. When the FUS protein is made from mutated FUS genes, they are located in the cytoplasm and are clumped together. The clumps are associated with degeneration of nerve cells and are found in a rare form of familial ALS that is caused by mutations in the TDP43 gene (Naganska & Matyja, 2011). Mutations in both TDP43 and FUS gene occur in about four to five percent of familial ALS cases.

Moreover, the SMN gene, which is located in chromosome 5q has also been associated with ALS. The SMN gene is found all over in the body but is concentrated in the spinal cord. It is essential for the maintenance of the viability of motor neurons in the spinal cord. SMN gene also plays an indispensable role in the processing of mRNA. The lack of mature mRNA production results in the disruption in cell growth and function. Motor neurons are sensitive to this abnormality and die prematurely (Naganska & Matyja, 2011). An increased abnormal number of SMN1 genes is believed to cause ALS. The abnormal genes alter the amount of SMN protein that is produced.

Inflammation is another significant cause of ALS. Cells that cause inflammation and end up causing ALS are the T-regulatory lymphocytes (Tregs). Tregs are essential immunomodulatory cells that regulate the balance between activation and suppression of the immune response and control the microglia in the central nervous system. They ensure repair and remodeling activities are activated. However, defects of Tregs have been found in patients with ALS and become frequent as the disease progresses (Martin, Khleifat, & Al-Chalabi, 2017). The survival of patients with ALS becomes more difficult when they have defects in Tregs.

Poliovirus and other enteroviruses, and HIV can cause ALS. Studies of serum and cerebrospinal fluid from ALS patients indicated that an activated endogenous retrovirus

was associated with ALS (Martin, Khleifat, & Al-Chalabi, 2017). The sequence was identified as HERV-K, which is an endogenous retrovirus in the human genome. In mice, the protein component of HERV-K has been found to be toxic to motor neurons.

ALS can also be inherited from one family member to another. Studies indicate that the heritability of ALS genes is sixty percent (Martin, Khleifat, & Al-Chalabi, 2017). A significant number of individuals have been found to carry variants of ALS, which are C9orf72,

TBK1, and NEK1. Although carrying the disease variant does not mean ALS, will follow but is an indication of manifestation of the disease at a later time. These gene variants are rare but have a substantial contribution to the disease. Besides, studies have also indicated environmental risks as primary causes of ALS. The ecological causes of ALS have been challenging to identify because the research is expensive and require a lot of funding. Several studies have associated smoking to cause ALS. Other studies have also identified occupations such as military can cause ALS. Military service with deployment is associated with ALS, and the data for the study was obtained from the U.S., which has an enormous dataset of military personnel (Martin, Khleifat, & Al-Chalabi, 2017). Increased physical activity is another studied risk factor for ALS. A significant number of high-profile sports players have been diagnosed with ALS. Researchers believe that the high levels of physical activity raise the risks of ALS.

Symptoms and Diagnosis of ALS

A majority of ALS cases indicate asymmetric focal appendicular weaknesses are progressing with bulbar dysfunction, quadriparesis, and respiratory insufficiency leading to death (Souza, Pinto, Chieia, & Oliveira, 2015). Cognitive and behavioral disturbances are also frequent among ALS patients. Progressive muscle weaknesses in hands, arms, legs, and the muscles responsible for speech articulation swallowing and breathing are characteristics of ALS (Naganska & Matyja, 2011). Sixty percent of ALS patients indicate muscle weakness as an initial sign of ALS. The hands and feet are affected causing difficulty in lifting and holding objects and performing simple chores such as dressing. Muscle weakness the leads to fasciculation and cramping of muscles.

In a neurological examination, the following symptoms of ALS are observed impaired swallowing and impaired speech, Babinski's sign, hyperactive tendon reflexes, increased muscle tone, and spasticity (Naganska & Matyja, 2011). Twitching may occur in the tongue and other affected limbs. Patients may experience muscle pain and muscle cramps. A significant number of patients also have difficulties in swallowing saliva and other liquids.

Clinical diagnosis of ALS is based on based on signs of progressive upper and lower motor neuron dysfunction. However, researchers have failed to develop a single diagnostic strategy that can be used to deduce or exclude the presence of ALS in a patient. Overall, a comprehensive diagnostic test involves electrodiagnostic tests such as electromyography (EMG) and nerve conduction velocity (NCV) (Naganska & Matyja, 2011). Other tests that can be used for the diagnosis of ALS include magnetic resonance imaging (MRI scan). This test may be utilized to rule out spinal cord or brain stem disease. Equally important, blood tests may be essential for the detection of abnormal proteins and the presence of metals such as lead, which is associated with various neurological diseases.

Treatments

As stated earlier the treatments of ALS mainly consist of medications that aid in slowing down the disease ultimately trying to prolong life. However, according to the American Journal of Hospice and Palliative Medicine, the few drugs out there like Riluzole, an FDA approved drug lack therapeutic effectiveness. Ideally, for a drug or a regimen to help ALS patients, it should include glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators, an antiapoptic agent, one or more neurotrophic growth factors, and a mitochondrial function-enhancing agent. One substance that seems to be active in all those areas is cannabis (Carter, Abood, Aggarwal, & Weiss, 2010, 1). Marijuana has anti-oxidative, anti-inflammatory, and neuroprotective effects (Carter, Abood, Aggarwal, & Weiss, 2010, 1). It can also manage daily symptoms such as loss of appetite, depression, spasticity, pain, and drooling (Weydt et al., 2005).

Cannabis is a complex plant consisting of 400 chemicals. About 60 of these chemicals are cannabinoi...