Simple models to understand complex disease: 10 years of progress from Caenorhabditis elegans models of amyotrophic lateral sclerosis and frontotemporal lobar degeneration

Abstract

The nematode Caenorhabditis elegans are a powerful model system to study human disease, with numerous experimental advantages including significant genetic and cellular homology to vertebrate animals, a short lifespan, and tractable behavioral, molecular biology and imaging assays. Beginning with the identification of SOD1 as a genetic cause of amyotrophic lateral sclerosis (ALS), C. elegans have contributed to a deeper understanding of the mechanistic underpinnings of this devastating neurodegenerative disease. More recently this work has expanded to encompass models of other types of ALS and the related disease frontotemporal lobar degeneration (FTLD-TDP), including those characterized by mutation or accumulation of the proteins TDP-43, C9orf72, FUS, HnRNPA2B1, ALS2, DCTN1, CHCHD10, ELP3, TUBA4A, CAV1, UBQLN2, ATXN3, TIA1, KIF5A, VAPB, GRN, and RAB38. In this review we summarize these models and the progress and insights from the last ten years of using C. elegans to study the neurodegenerative diseases ALS and FTLD-TDP.

Keywords: C. elegans; C9orf72; FUS; SOD1; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; neurodegeneration.

Figure 1

Strategies to model TDP-43-driven ALS and FTLD-TDP in C. elegans. (A) Manipulation of the endogenous C. elegans ALS gene homolog through introduction of fALS mutations at conserved loci, protein overexpression, human-worm gene chimeras, or loss-of-function mutations. (B) Generation of transgenic C. elegans expressing full-length wild-type or mutant human protein, select protein domains, or a single-copy insertion of the human gene into the genome, potentially replacing the endogenous worm homolog. (C) C. elegans model utility for a broad range of unbiased and hypothesis driven research including drug screening, fALS mutation characterization, cellular and molecular pathway exploration, protein post-translational modifications, and genome-wide applications including forward and reverse genetics approaches.