page_title: Amyotrophic lateral sclerosis
section_title: Model organisms
hierarchical_section_title: Amyotrophic lateral sclerosis / Research / Model organisms
caption_attribution_description: English: This is a cropped image of a chart from the journal article "Modelling amyotrophic lateral sclerosis: progress and possibilities". Fig. 2. Model systems in ALS research. A summary of the advantages and limitations of the different model systems – yeast, C. elegans, Drosophila, zebrafish, rodents and iPSC-derived neurons – currently used to study ALS.
context_page_description: Amyotrophic lateral sclerosis, also known as motor neurone disease or Lou Gehrig's disease, is a disease that causes the death of neurons controlling voluntary muscles. Some also use the term motor neuron disease for a group of conditions of which ALS is the most common. ALS is characterized by stiff muscles, muscle twitching, and gradually worsening weakness due to muscles decreasing in size. It may begin with weakness in the arms or legs, or with difficulty speaking or swallowing. About half of the people affected develop at least mild difficulties with thinking and behavior and most people experience pain. Most eventually lose the ability to walk, use their hands, speak, swallow, and breathe.
  The cause is not known in 90% to 95% of cases, but is believed to involve both genetic and environmental factors. The remaining 5–10% of cases are inherited from a person's parents. About half of these genetic cases are due to one of two specific genes. The underlying mechanism involves damage to both upper and lower motor neurons. The diagnosis is based on a person's signs and symptoms, with testing done to rule out other potential causes.
  No cure for ALS is known.
context_section_description: Many different organisms are used as models for studying ALS, including Saccharomyces cerevisiae (a species of yeast), Caenorhabditis elegans (a roundworm), Drosophila melanogaster (the common fruit fly), Danio rerio (the zebrafish), Mus musculus (the house mouse), and Rattus norvegicus (the common rat). None of these models perfectly represents ALS in humans, partly because most animal models are based on gene overexpression, meaning that multiple copies of the mutant human gene are inserted into the transgenic model, and partly because the human nervous system is very different from that of other animals.
  The first animal model for ALS was the SOD1ᴳ⁹³ᴬ transgenic mouse, which was developed in 1994. It expresses about 20–24 copies of the mutant human SOD1 gene and reproduces most of the clinical and pathological findings seen in ALS. Although there are now over 20 different SOD1 mouse models, the SOD1ᴳ⁹³ᴬ model remains both the most widely used SOD1 mouse model and the most widely used ALS mouse model overall. Much of the present understanding of ALS pathophysiology came from studying mouse models that overexpress mutant SOD1, especially SOD1ᴳ⁹³ᴬ mice. However, many drug targets that were shown to be effective in the SOD1ᴳ⁹³ᴬ transgenic mouse failed in clinical trials in humans; other SOD1 models have had similar problems. Most of these drugs were identified as potentially effective based on a single study in a rodent SOD1 model and then failed in clinical trials in patients who primarily had sporadic ALS. It is thought that these clinical trials failed because SOD1 mutations account for only 2% of all ALS cases and because the pathology of SOD1 ALS is thought to be distinct from all other types of ALS; it lacks the abnormal aggregations of TDP-43 protein or FUS protein seen in nearly all other cases of ALS.
  As of 2018, there are about 20 TARDBP mouse models, a dozen FUS mouse models, and a number of C9orf72, PFN1, and UBQLN2 mouse models. There are also new methods of developing animal models, including viral transgenesis, in which viruses are used to deliver mutant genes to an animal model, and CRISPR/Cas9, which can be used to give an animal model multiple mutated genes. Both of these methods are faster and cheaper than traditional methods of genetically engineering mice; they also allow scientists to study the effects of a mutation in mice of different genetic backgrounds, which better represents the genetic diversity seen in humans.
  Cellular models used to study ALS include the yeast Saccharomyces cerevisiae and rat or mouse motor neurons in culture. Small-animal models include the fruit fly, the roundworm C. elegans, and the zebrafish. Of the three, the fruit fly is the most widely used; it has a rapid life-cycle, short lifespan, a sophisticated nervous system, and many genetic tools available. C. elegans has a short life-cycle, is easy to manipulate genetically, and has a simple but well-understood nervous system. The zebrafish has transparent embryos that can be injected with DNA or RNA and has a lifespan of up to two years. Induced pluripotent stem cells (iPSCs) can be used to convert skin fibroblasts into motor neurons. It is now possible to generate iPSCs from people with ALS, which can then be converted into spinal motor neurons, which are useful for studying disease mechanisms and for testing potential drugs for ALS. iPSCs allow sporadic ALS to be modeled, which cannot be done with animal models.
caption: Some of the most common models used to study ALS.
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