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Review
. 2018 Sep-Oct;32(5):983-998.
doi: 10.21873/invivo.11339.

From Mouse Models to Human Disease: An Approach for Amyotrophic Lateral Sclerosis

Aziza Rashed Alrafiah  1
Affiliations
Review

From Mouse Models to Human Disease: An Approach for Amyotrophic Lateral Sclerosis

Aziza Rashed Alrafiah. In Vivo. 2018 Sep-Oct.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There are several genetic mutations that lead to ALS development, such as chromosome 9 hexanucleotide repeat 72 (C9ORF72), transactive response DNA-binding protein (TARDBP), superoxide dismutase 1 (SOD1) and fused in sarcoma (FUS). ALS is associated with disrupted gene homeostasis causing aberrant RNA processing or toxic pathology. Several animal models of ALS disease have been developed to understand whether TARDBP-mediated neurodegeneration results from a gain or a loss of function of the protein, however, none exactly mimic the pathophysiology and the phenotype of human ALS. Here, the pathophysiology of specific ALS-linked gene mutations is discussed. Furthermore, some of the generated mouse models, as well as the similarities and differences between these models, are comprehensively reviewed. Further refinement of mouse models will likely aid the development of a better form of model that mimics human ALS. However, disrupted gene homeostasis that causes mutation can result in an ALS-like syndrome, increasing concerns about whether neurodegeneration and other effects in these models are due to the mutation or to gene overexpression. Research on the pleiotropic role of different proteins present in motor neurons is also summarized. The development of better mouse models that closely mimic human ALS will help identify potential therapeutic targets for this disease.

Keywords: Amyotrophic lateral sclerosis; C9ORF72; FUS; SOD1; TARDBP; motor neuron diseases; mouse models; review.

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Figures

Figure 1
Figure 1. Pathogenesis of C9OR72-, TARDBP-, SOD1-, and FUS-associated amyotrophic lateral sclerosis (ALS). A: Chromosome 9 hexanucleotiderepeat72 (C9ORF72) 2 mutation acts through a gain-of-function (GOF) mechanism. GGGGCC[G4C2] is translocated to the cytosol and then eithertranslated to form aggregates of poly-(GP) dipeptide-repeat proteins (DPR) or misfolded to form aggregates of ubiquitinated (U) RNA foci associatedwith TDP43 or FUS proteins, which both mediate neuronal toxicity. B: transactive response DNA-binding protein (TARDBP) mutation acts throughboth loss of function (LOF) and GOF mechanisms. Normal TDP43 function is lost due to mutant (mt) TDP43 proteins inhibiting normal TDP43from binding to pre-mRNA. C: superoxide dismutase 1 (SOD1) mutation acts through a GOF mechanism. Mutant SOD1 dimers in the cytosolaccumulate as SOD1 inclusions within mitochondria and Lewy-body-like hyaline (LBLH) inclusions in the cytosol where they can triggermitochondrial reactive oxygen species (ROS) generation later, causing mitochondrial destruction. D: fused in sarcoma (FUS) mutation acts throughboth LOF and GOF mechanisms. Mutant FUS proteins cause LOF by inhibiting normal FUS from binding to pre-mRNA. E: Cytosol vacuolizationis caused by all the above-mentioned mutations.
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