Laboratory models of ALS help researchers understand the basic processes of the disease, which is essential for developing new therapies. Important lab models in ALS include cells, worms, flies, fish, mice, and rats. No model is a perfect representation of the human disease, but each model offers advantages for studying some aspect of it. Many of the same models are used to test new therapies to find ones promising enough to bring to clinical trial in ALS patients.
Most ALS disease models begin with a mutated gene known to cause disease in humans. Using the techniques of molecular biology, the gene is inserted into the model organism. Ideally one would prefer to express the mutated gene at levels comparable to that in humans, however in most cases where expression of these mutated proteins is at low levels, disease does not manifest in the model system. The gene is therefore often “overexpressed,” that is, stimulated to make more protein than usual, in order to speed up the disease process.
Motor neurons in a dish are useful for studying the response of individual cells to toxins or potential therapies. Motor neurons carrying the mutant SOD1 gene have been used to study the process of protein aggregation, which researchers believe is harmful to motor neurons. Motor neurons can be grown together with astrocytes, which are cells in the brain that help support neurons, but may also deliver toxic molecules to motor neurons in ALS.
Exciting new opportunities have opened up with the development of induced pluripotent stem cells (iPS cells). These cells can be derived from the skin of an ALS patient, genetically modified and used to generate motor neurons in a dish. This should allow researchers to gain a deeper understanding of the disease process as it differs among different patients.
Cell models are especially useful for rapid, “high-throughput” screening of thousands of compounds to discover drugs that may alter the disease process, potentially leading to new therapies.
The roundworm C. elegans is one of the simplest of animals. It has only 959 cells, and a three-day life cycle. Its simple structure, short lifespan, and transparent body make it possible to study development of its motor neurons in detail in a short amount of time.
The fruit fly shares many of the same characteristics. Its nervous system is more complex, and it has been possible to discover flies with mutations that lead to symptoms reminiscent of ALS. Additionally, known ALS genes, when bred into the fruit fly, can produce visible manifestations in the fly. The flies can then be used to screen drugs that may improve those manifestations, potentially leading to new treatments for the disease
The zebrafish is a small, rapidly breeding freshwater fish that is easy to grow in the lab. As a vertebrate, it shares many developmental and anatomical features with humans. Screening for mutations that interrupt normal motor neuron function has led to new clues about vulnerabilities of motor neurons. ALS genes can be inserted into the zebrafish, and its effect on motor neurons studied.
The mouse bearing the human gene for mutant SOD1 was the first lab model for ALS based on a known cause of the disease. It remains the most widely used animal model of the disease. The SOD1 rat is also available, and because it is larger, is preferred when surgery is involved (such as for cell transplantation approaches). Rodents are especially important for testing potential therapies, since their nervous systems are much larger and more complex than other animal models.
Several rodent models based on the TDP-43 gene have recently been developed, and others incorporating the FUS gene or the C9ORF72 gene are in the works. All will undoubtedly enable rapid progress in finding new ways to approach ALS treatment.
Updated, July 2012