Worming forward: amyotrophic lateral sclerosis toxicity mechanisms and genetic interactions in Caenorhabditis elegans

Abstract

Neurodegenerative diseases share pathogenic mechanisms at the cellular level including protein misfolding, excitotoxicity and altered RNA homeostasis among others. Recent advances have shown that the genetic causes underlying these pathologies overlap, hinting at the existence of a genetic network for neurodegeneration. This is perhaps best illustrated by the recent discoveries of causative mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Once thought to be distinct entities, it is now recognized that these diseases exist along a genetic spectrum. With this wealth of discoveries comes the need to develop new genetic models of ALS and FTD to investigate not only pathogenic mechanisms linked to causative mutations, but to uncover potential genetic interactions that may point to new therapeutic targets. Given the conservation of many disease genes across evolution, Caenorhabditis elegans is an ideal system to investigate genetic interactions amongst these genes. Here we review the use of C. elegans to model ALS and investigate a putative genetic network for ALS/FTD that may extend to other neurological disorders.

Caenorhabditis elegans models of tauopathy

“…Although higher animal models (e.g., mice or rats) mimic the human nervous system more closely, the major advantage of lower animal models like C. elegans in unraveling the molecular pathways causing these diseases is the availability of strong genetic and imaging tools, combined with the short lifespan and low cost. Indeed, C. elegans studies have increased our understanding of the aging process and of many human diseases such as AD, Parkinson disease, cancer, depression, and diabetes to name a few (30,32,133). Because most of the pathways are conserved between worms and mammals, C. elegans models will help to explore the effects of drugs with an ultimate aim of developing therapeutic interventions for humans.…”

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

“…Over twodozen genes are associated with ALS, including genes encoding the DNA/RNA-binding proteins TAR DNA Binding Protein 43 (TDP-43) and fused in sarcoma (FUS) 3 . A great challenge remains in functionally linking these ALS mutations to pathogenic mechanisms, and with the recent discovery of so many new genes comes the need to develop experimentally tractable models 4 .…”

“…elegans possesses an innate immune system that is induced in response to viral or microbial infection 13 . One antimicrobial defence pathway in C. elegans consists of tir-1, encoding a Toll Interleukin 1 Receptor (TIR) domain adaptor protein, which is orthologous to human Sarm1 (sterile alpha and armadillo repeats) 14 C. elegans is an established model for investigating conserved genetic pathways that regulate the cellular stress response and neurodegeneration 4 . In this study, using transgenic C. elegans models for ALS we investigate the role of the innate immune response and discover that the TIR-1 pathway regulates motor neuron degeneration caused by mutant TDP-43 and FUS proteins.…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…The most frequent mutations are found in C9orf72 (10-15% of familial cases), the superoxide dismutase SOD1 enzyme (2%), the TDP-43 protein, which is a component of the ubiquitin-containing aggregates that appear in the motor neurons (0.9%), and the FUS protein (RNA-binding protein Fused in Sarcoma, 0.7%), although mutations in many other genes have been found to be associated with this disease. C. elegans has orthologues of all these four genes, and C. elegans models of mutations in these genes have been recently made, both by expressing mutant forms of the human proteins or by mutating the corresponding worm orthologues [7,9,14,24,25].…”