Capstone Project: Familial ALS

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder affecting motor neurons in the brain and spinal cord, which leads to terminal paralysis. The disease is caused by several factors, one of which is genetics, meaning it is inherited. This form of ALS, called ALS1 or familial ALS (FALS), is the result of a change in one of many different proteins in the nerve cell. The CDC estimates that 14,000-15,000 Americans are living with ALS at any given time, with about 10% of those having ALS1 (Siddique and Siddique 1993). The peculiar thing about the types of ALS is that the genes and environmental factors that cause them are completely diverse, but the symptoms one experiences, called the clinical phenotypes, are virtually the same. This is because they all disrupt the cellular balance, called homeostasis, in motor neurons, specifically the ALS pathway. I investigated the disease mechanism for FALS within the context of a specific biomolecule. This post gives a brief overview of how FALS begins and what can be done to mitigate symptoms.

The most researched protein linked to ALS is the copper-zinc superoxide dismutase, or SOD1 for short. This protein in an oxidoreductase, meaning it is a biological catalyst that facilitates a chemical reaction involving the transfer of electrons. SOD1 uses a reactive copper ion to reduce oxidative stress on the cell, sort of like antioxidants do except SOD1 is a catalyst, so it is reusable. In its unmutated, normal state, SOD1 detoxifies the cell of the superoxide radical, which causes major damage to biomolecules (Mondola et al. 2016). Normally, that is all it does, but in FALS, it has a more destructive role.

In the vast majority of cases, defective SOD1 retains its ability to detoxify the cell of superoxide but gains the ability to form aggregates and hold onto hydrogen peroxide for longer. This is called a gain-of-function mutation because the enzyme can perform a secondary function without significantly impairing the primary function. In some SOD1 mutant proteins, the Km value for hydrogen peroxide, one of SOD1’s products, is lowered, meaning the enzyme has higher affinity for hydrogen peroxide. This makes it easier for hydrogen peroxide to decompose into the highly toxic hydroxyl radical, which causes high levels of oxidative stress (Mondola et al. 2016). The mutant proteins are more prone to aggregation, which can disrupt mitochondria, the powerhouse of the cell (DiDonato et al. 2003). In addition to reducing the cell’s ability to extract free energy in the form of ATP, disabling mitochondria releases calcium ions and starts a cascade of signaling that quickly spirals out of control. This all sends signals to the cell to promote apoptosis, a form of programmed cell death. Once the nerve cell is dead, it is unable to transmit more signals, resulting in the loss of voluntary movement to a part of the body. The ALS pathway is complicated and probably incomplete; for a flowchart of all the known interactions, click this link to an outside website.

There is currently no cure for ALS. The ALS Association estimates that only about 20% of patients survive more than five years after diagnosis; this might be expected since ALS directly damages the central nervous system. The most common causes of death are pneumonia and respiratory failure because of weakened breathing, but choking is a persistent fear once the patient loses the ability to swallow. Hence, treatment is palliative: it is not usually hospice care, but it is not meant to cure (Siddique and Siddique 1993). All ALS treatment is meant to improve quality of life in the patient’s final years and to prevent untimely accidents when they lose control of their bodies.

A genetic test is not necessary to diagnose ALS, as ALS1 and sporadic ALS are treated the same way, irrespective of the chemical underpinnings. Nonetheless, there are two drugs that can improve quality of life and marginally increase lifespan in ALS patients. The first is riluzole, approved in 1999, which mitigates overstimulation of neurons by glutamate, a neurotransmitter. As shown in the ALS pathway, one of the ways ALS is exacerbated is by overstimulation from glial cells, so riluzole blocks this component, slowing the disease by an average of two months (Bensimon et al. 1999). Another drug, approved 2017, is edaravone. Edaravone is thought to act as a free radical scavenger, neutralizing the excess hydroxyl radicals made by mutant SOD1 (Abe et al. 2017).

Patients also benefit from a holistic mental health treatment from many psychological and medical professionals (Siddique and Siddique 1993). Patients can make their lives easier by taking antioxidant vitamin supplements and by eating purees or installing a feeding tube when the time comes. Treatment is imperfect, yes, but patients consistently say it helps.

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Thanks for reading my blog post! If you liked it or have any questions, feel free to leave a comment below. If you’re interested in a more elaborated, scientific perspective on familial ALS, you can visit my theme pages, linked to at the top of this website and directly below this post.

The first thing to do would be to visit my primer page, where you can orient yourself before diving into the theme pages:

Healthy State page.

Disease Mechanism page.

History & Symptoms page.

Treatment & Frontiers page.

All my citations are listed in the Annotated Bibliography, organized chronologically.

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