Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, multigenic, multifactorial, and non-cell autonomous neurodegenerative disease characterized by upper and lower motor neuron loss. Several genetic mutations lead to ALS development and many emerging gene mutations have been discovered in recent years. Over the decades since 1990, several animal models have been generated to study ALS pathology including both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs, and non-human primates. Although these models show different peculiarities, they are all useful and complementary to dissect the pathological mechanisms at the basis of motor neuron degeneration and ALS progression, thus contributing to the development of new promising therapeutics. In this review, we describe the up to date and available ALS genetic animal models, classified by the different genetic mutations and divided per species, pointing out their features in modeling, the onset and progression of the pathology, as well as their specific pathological hallmarks. Moreover, we highlight similarities, differences, advantages, and limitations, aimed at helping the researcher to select the most appropriate experimental animal model, when designing a preclinical ALS study.

SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines

“…The p.Gly94Ala mutation, known as G93A, was used to create the first ALS-associated SOD1 transgenic mouse. This model, which expresses large amounts of mutant SOD1 , develops adult-onset neurodegeneration of spinal motor neurons and progressive motor deficits leading to paralysis, and it is now widely used both for pathogenic molecular mechanisms and for preclinical studies useful for the specific therapy of affected patients [ 31 , 39 , 40 , 41 ]. This mutation is currently the one studied in the largest number of animal models including C. Elegans, Saccharomyces Cerevisiae, Swine, and Danio rerio (Zebrafish) models.…”

“…This mutation is currently the one studied in the largest number of animal models including C. Elegans, Saccharomyces Cerevisiae, Swine, and Danio rerio (Zebrafish) models. In the same way, experimental models of the transgenic mouse G93A and H46R (p.His47arg) show degeneration of the upper and lower motoneurons associated with a gravity directly proportional to the altered protein expression [ 31 , 39 , 42 ]. In addition, in vivo experiments show that SOD1 -D91A (p.Asp91Ala), the most common mutation affecting SOD1 linked to ALS, is less toxic than other tested mutants, while homozygous mice develop fatal motor neuron disease similar to that observed in homozygous-D91A human ALS patients [ 41 , 43 ].…”

“…A Zebrafish model with G94R (p.Gly94Arg) variant has been developed, and this shows a mutated expression of SOD1 at a physiological level, which allows targeted pre-clinical studies [ 31 , 49 ]. For the variants G86R (p.Gly86Arg) [ 31 , 45 , 46 , 47 ] and G38R (p.Gly38Arg) [ 31 , 47 , 48 ], there are several functional studies carried out on transgenic mouse models in which there are high expression levels of the mutated gene and differences in the age of onset and progression of the disease as well as lifespan. For the G86R variant, studies have also been carried out using the C. Elegans nematode model.…”

“…Current understanding indicates that there may be a complex interplay between genetic factors, oxidative stress, excitotoxicity, protein aggregation, impaired axonal transport, and mitochondrial damage. Over the years, several in vitro and in vivo experimental models have been exploited to study the molecular processes underlying motor neuron degradation and disease progression, providing essential small pieces to the ALS puzzle [ 31 , 32 ]. However, only an integrated and complimentary use of different experimental models could improve our understanding of the pathogenic mechanism of the disease.…”

Therapeutic Targets in Amyotrophic Lateral Sclerosis: Focus on Ion Channels and Skeletal Muscle

“…Other mutations in several genes, such as ANG (angiogenin), DCTN1 (dynactin), TDP43 (TAR DNA-binding protein 43), FUS (protein Fused in Sarcoma), and C9orf72 (chromosome 9 open reading frame 72) were linked to familial forms of ALS [4]. In the last years, several animal models were generated by reproducing various mutations, with the aim of studying this pathology and the involvement of various tissues [5]. Actually, clinical symptoms and the pathogenic mechanisms were found to be the same in sporadic and familial cases of ALS.…”