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What causes ALS?

Understanding the causes and mechanisms of motor neurone degeneration is essential to allow the development of treatments. Only by understanding what goes wrong in ALS can scientists know how to design and where to target drugs and other therapies.

At the moment, the cause of ALS is still not fully understood. The majority of ALS cases are thought to be caused by a number of contributory factors, including subtle genetic, environmental and lifestyle influences. There are several research studies investigating possible risk factors that may be associated with ALS.

Exposure to lifestyle and environmental factors that might contribute to the development of ALS has been extensively studied over the years. This research is known as epidemiology. Epidemiological studies have identified possible links with prior exposure to mechanical and/or electrical trauma, military service, smoking, agricultural chemicals, high levels of physical activity, and a variety of heavy metals. However, it is important to note that these are only suspected contributory risk factors and the evidence obtained in these studies has often not been conclusive. More work is needed to conclusively determine what genetics and/or environment factors contribute to developing ALS. One possible explanation is that they have a cumulative effect in weakening of nerve cells, making them more susceptible to degeneration. Another explanation is that these factors interact with specific genes, triggering the disease through gene-environment interactions.

The six steps theory

Using a mathematical model, previously used by cancer researchers, Al-Chalabi and colleagues (2014) suggested that it takes six steps to trigger ALS. The number of steps might be different (and likely reduced) in ALS caused by specific genes. Each step represents a separate event that could be a genetic, environmental or lifestyle factor with the last one triggering the disease. What exactly these factors are is yet unknown.

Al-Chalabi et al. Lancet Neurol. 2014 Nov 13; 13(11): 1108–1113.


According to the multistep hypothesis, the six steps necessary to develop ALS reduce to four in people with TARDBP gene mutation, three in C9ORF72, and two in SOD1. Modified from https://mndresearch.blog/2018/08/03/steps-to-understanding-mnd/

Genetics

Genes are strings of DNA that provide instructions, or code, for making proteins. Proteins are the principle components of all types of cells, controlling reactions and providing structure. Genes, which we inherit from our parents, contain the information needed to our body to develop and function. In approximately 10% of cases, ALS is directly caused by a genetic mistake, called mutation. Mutations can cause the cell to make either too little protein, or too much protein, or a defective protein. Different mutations may cause different effects. Any change in the normal protein can be harmful to the cell, and may cause disease. A mutation may also be harmful not because it changes the protein encoded by the gene, but due to its effect on RNA. RNA is an intermediary, or messenger, between gene and protein. To make a protein, the cell first uses the DNA gene to form an RNA copy. That copy is then used to provide the “working instructions” to make the protein. After it is formed and before it is used to make protein, RNA is processed in several different ways. Mistakes in RNA processing may cause disease.

Mutations can be passed down from parent to child, so the disease appears in the different generations of a family. This is known as familial, or inherited ALS. Inheriting a copy an ALS-causing gene however doesn’t necessarily mean that the person will go on to develop the disease, and the influence of the contributory factors is still likely to play a role.

In the majority of cases however, the disease appears for no apparent reason and without any known familial link. This form of the disease is known as sporadic ALS. Normal genetic variations may make people more susceptible, but this type of ALS is thought to result from a combination of subtle genetic, environmental and lifestyle factors. Researchers believe that discovering the genetic causes of inherited ALS will lead to a better understanding of what is going wrong in all forms the disease.

There is vast heterogeneity in the genetic causes of familial ALS, but familial and sporadic ALS have similarities in their pathological  and clinical features (they are clinically indistinguishable), suggesting a convergence of the cellular and molecular events that lead to motor neuron degeneration.

We know today the four major genes involved (SOD1, TDP-43, FUS, C9orf72) and more than 15 minor genes (i.e. ALS2, SETX, VAPB, FIG4, ERBB4, MATR3, ANG, OPTN, VCP, UBQLN2, CHMP2B, PFN1, hNRPA1 A2/B1, TUBA4A, NEK1, UNC12A, ANXA11). The mutations identified to date are responsible for about 70% of familial cases and about 12% of sporadic cases.

ALS Gene Discovery since 1990. From Robert H. Brown and Ammar Al‑Chalabi, N Engl J Med 2017;377:162-72.

Main genes that cause ALS

C9ORF72 This gene, discovered in 2011, is the most common genetic cause of ALS. (Its name refers to the position of an “open reading frame” on chromosome 9). Mutations in this gene account for between 25% and 40% of all familial ALS cases (depending on the population), and also approximately 4% to 6% of sporadic cases. This gene also causes another neurodegenerative disease, called frontotemporal dementia (FTD). Some people with this gene will develop symptoms only of ALS, some only of FTD, and some will have symptoms of both disorders. How this gene causes ALS is unknown, and is the subject of a great deal of intense research.

Cu/Zn Superoxide Dismutase 1 (SOD1) Mutations in SOD1 were first described in 1993, and SOD1 was the first gene known for ALS. It accounts for about 10% of familial ALS, or 1.5% to 2% of all ALS. How SOD1 mutations cause ALS is unknown. It is clear that disease is not due only to lack of function of the protein, since deleting the gene in animal models doesn’t cause ALS. Instead, it appears to take on some new toxic function, possibly related to an increase in the tendency of mutant SOD1 molecules to aggregate and form clumps in motor neurons. It is also possible that SOD1 causes ALS through actions in nearby cells called astrocytes, not in motor neurons themselves. Astrocytes are glial cells that surround motor neurones, providing them support and nourishment, and SOD1 mutation may impair their ability to do so.

TDP-43 TAR DNA binding protein 43 (TARDP-43) was linked to ALS in 2008. The normal role of the TDP-43 protein includes binding to RNA, the genetic messenger molecule. Mutations in the TDP-43 gene cause the TDP-43 protein to mislocalize in motor neurons, away from the nucleus where it is normally found, and into the cytoplasm (the material surrounding the nucleus), where it aggregates into clumps that can be seen under the microscope. Even in ALS not caused by TDP-43 mutations, the protein is found in these aggregates, suggesting it may play a pivotal role in many forms of ALS.

FUS Fused in sarcoma (FUS) was also discovered to play a role in ALS in 2008. Like TDP-43, it is also an RNA binding protein, and may play a similar normal role in the cell. FUS and TDP-43 may in fact interact as part of their normal function.

Source: www.mndassociation.org and www.alsa.org

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