ALS In Vitro Disease Models

Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disease after Alzheimer's disease and Parkinson's disease, and there is still no effective treatment now. With an experienced expert team, Creative Biolabs is devoted to helping customers optimize their schemes and providing quality-assured ALS in vitro models and one-stop neuroscience research services to global clients.

Targets and Mutations Involved in ALS

Gene mutation is an important cause of disease pathogenesis. Recently, multiple mutations have emerged as the main research targets in different ALS manifestations. Genes related to RNA metabolism, cellular transport, axonal outgrowth, protein metabolism, glutamatergic signaling, angiogenesis, neurotransmission, or with antioxidant function were already identified.

• SOD1 mutation

Among the mutations studied, some are observed in the gene encoding a Metallo cytosolic homodimeric enzyme, Cu/Zn superoxide dismutase (SOD1), which catalyzes the dismutation of the superoxide anion in oxygen and hydrogen peroxide. Given this function, the toxicity of the different mutated forms of SOD1 could result from decreased elimination of free radicals; however, there is great variation in these proteins' enzymatic activity. SOD1 mutations lead to motor neuron death through the gain of toxic properties because of malformed proteins, protein aggregates, and reactive oxygen species, among others.

• TARDBP mutation

Mutations in the TARDBP gene, which encode the TAR DNA-binding protein 43 (TDP-43), were also reported. TDP-43 has been one of the main proteins found in protein aggregates presenting in the cytoplasm of motor neurons in ALS cases. In addition, this proteins' loss of function impairs axonal transport, which is also associated with neurodegeneration.

• FUS/TLS mutation

Mutations in the FUS/TLS gene, which encodes the RNA-binding protein, sarcoma fusion protein (FUS), were also involved in the disease pathogenesis. This protein is normally located in the cell nucleus, but mutated forms are found aggregated in the cytoplasm of nerve cells. Protein aggregate are a pathogenic mechanism that leads to the death of motor neurons in ALS.

• C9ORF72 and other mutations

The recently-identified repeated expression of hexanucleotide "GGGGCC" in the C9ORF72 gene's non-coding region was associated with different forms of the disease, suggesting that the toxicity in these nucleotides' RNA is related to the neurodegeneration in the presence of C9ORF72. Currently, in European populations, this mutation is known to be more common than the SOD1 gene mutation and three times more common than the mutations in TDP-43 and FUS. Other, less frequent, genetic mutations are also involved in some cases of ALS, such as VABP, OPTN, VCP, UBQLN2, MATR3, TBK1, NEK1, and C21ORF2, among others. About 30 gene mutations have already been described.

Fig.1 G₄C₂ repeat expansions in a non-coding region of C9ORF72. (Kim, 2020)

In Vitro Models of ALS

A great deal of the knowledge about ALS's pathological mechanisms comes from studies in cell culture models since less complex systems allow a greater understanding of more specific cellular mechanisms. Induced pluripotent stem cells (iPSCs) are a new model approach for fALS and sALS and represent a turning point in developing experimental disease models. iPSCs could help to define disease mechanisms and therapeutic strategies as they could be differentiated into motor neurons. In vitro models have been widely used by scientists owing to the advantages presented: controlled environment, single system, individual cell or tissue mechanisms, genetic manipulations, easy of culture, few variables, and minimizes the use of animals. Based on different targets and mutations involved in ALS, Creative Biolabs has developed various engineered cell lines as ALS in vitro models for research.

Creative Biolabs has been focusing on neuroscience research for years. Based on our extensive project experience and comprehensive platforms, we are confident in offering customers quality assured ALS in vitro models and related services. If you are interested in ALS in vitro models, or any other neuroscience research services, please don't hesitate to contact us for more information.

Reference

1. Kim, G.; et al. ALS Genetics: Gains, Losses, and Implications for Future Therapies. Neuron. 2020, 108(5): 822-842.