Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons in the brain and spinal cord. As these neurons die, the brain loses its ability to initiate and control muscle movement. To understand ALS and develop treatments, scientists use animal models, with mice being particularly important. The genetic similarities to humans and a mouse’s short lifespan allow researchers to observe a full disease course in months rather than years.
Decades of research have also produced sophisticated tools for genetic engineering in mice. This enables scientists to create models that replicate specific aspects of human ALS, providing a platform to study disease progression and test new therapies before human trials.
The Role of Mouse Models in ALS Research
Mouse models are designed to replicate the defining characteristic of ALS: the progressive loss of motor neurons. This is achieved by introducing a specific genetic mutation known to cause ALS in humans into the mouse’s genome. The resulting animals can then be studied to observe how the disease develops and progresses over their lifetime.
A successful model will exhibit symptoms that parallel those in human patients, such as muscle weakness, atrophy, and a shortened lifespan. For instance, a mouse may lose its grip strength or have difficulty moving, which corresponds to motor impairments in people with ALS. By studying these animals, scientists gain insights into the underlying biological processes that drive the disease.
These models are a platform for testing potential treatments. Researchers can administer a therapy to ALS mice and compare their outcomes to a control group. This allows them to assess whether the treatment can slow symptom onset, improve motor function, or extend lifespan. The data gathered is necessary for determining if a potential treatment is safe and effective enough for human clinical trials.
Common Genetic Mouse Models of ALS
The discovery of genes associated with familial ALS has led to several genetic mouse models. Each is based on a different gene mutation and provides unique insights into the disease. By comparing findings from each model, scientists can piece together a more complete picture of the molecular mechanisms at play.
- SOD1 models were the first to be created and are still widely used. These mice are engineered to carry a mutation in the human superoxide dismutase 1 (SOD1) gene, which is responsible for a form of inherited ALS. They develop many classic symptoms, including progressive muscle weakness and motor neuron degeneration.
- TDP-43 models address the mislocated and clumped TDP-43 protein found in the majority of ALS cases. Researchers developed mice that either produce a mutated form of the human TDP-43 gene or overproduce the normal protein. These models help explain how TDP-43 dysfunction contributes to motor neuron death.
- C9orf72 models are based on the most common genetic cause of ALS. These models are more complex to create because the mutation involves a repeated DNA sequence that is difficult to replicate in mice. They are being developed to help scientists understand how this specific flaw leads to the disease.
- FUS models are based on mutations in the FUS gene, another cause of familial ALS. These transgenic models have been shown to exhibit neurological issues and impaired motor function that mimic the human condition.
Key Research Applications
Mouse models of ALS are used to understand the mechanisms of the disease and to test potential therapies. By studying these mice, researchers can track disease progression at a cellular and molecular level. This allows them to identify events in the disease process, such as protein aggregation within neurons, nervous system inflammation, and problems with cellular energy production.
By examining the tissues of ALS mice at different disease stages, scientists can observe how and when motor neurons begin to die. They can also study the role of other cell types, such as glial cells, which support neurons and contribute to the progression of ALS. This detailed biological understanding helps identify potential targets for new drugs.
The other major application is preclinical therapy testing. In carefully controlled studies, some mice receive a potential treatment while others receive a placebo. Researchers then compare outcomes, looking for improvements in motor function, a delay in symptom onset, or an extension of the mouse’s lifespan. This process helps ensure that only the most promising treatments advance to human trials.
Challenges in Translating Findings to Humans
Despite their importance, there are challenges in translating findings from mouse models to humans. A primary reason is the genetic complexity of the disease. Most mouse models are based on single-gene mutations that cause familial ALS, which accounts for a small percentage of cases. Over 90% of ALS cases are sporadic, meaning their cause is unknown and likely involves a combination of genetic and environmental factors.
This genetic difference means a treatment effective in a mouse with a specific mutation may not work in a human with sporadic ALS. The models do not fully capture the genetic diversity of the human patient population. This has led to drugs showing promise in mice but failing in human clinical trials.
Physiological differences between mice and humans also impact how a disease progresses and how a drug works. Mice have a much faster metabolism, which can affect how a drug is processed. Their smaller size and shorter lifespan also mean the disease may progress differently than it does in people, which can sometimes lead to misleading preclinical results. Researchers are working to develop more sophisticated models that better reflect the complexity of human ALS.