Studying the mechanisms of neurodegeneration: C. elegans advantages and opportunities

Abstract

Caenorhabditis elegans has been widely used as a model organism in neurodevelopment for several decades due to its simplicity, rapid growth, short life cycle, transparency, and rather simple genetics. It has been useful in modeling neurodegenerative diseases by the heterologous expression of the major proteins that form neurodegenerative-linked aggregates such as amyloid-β peptide, tau protein, and α-synuclein, among others. Furthermore, chemical treatments as well as the existence of several interference RNA libraries, transgenic worm lines, and the possibility of generating new transgenic strains create a magnificent range of possible tools to study the signaling pathways that could confer protection against protein aggregates or, on the contrary, are playing a detrimental role. In this review, we summarize the different C. elegans models of neurodegenerative diseases with a focus on Alzheimer's and Parkinson's diseases and how genetic tools could be used to dissect the signaling pathways involved in their pathogenesis mentioning several examples. Finally, we discuss the use of pharmacological agents in C. elegans models that could help to study these disease-associated signaling pathways and the powerful combinations of experimental designs with genetic tools. This review highlights the advantages of C. elegans as a valuable intermediary between in vitro and mammalian in vivo models in the development of potential new therapies.

Keywords: C. elegans; advantages and disadvantages; genetic modulation; models; neurodegeneration; pharmacological treatment.

Figure 1

Procedure for crossbreeding. Crossbreeding between two different genotypes is made following a sequential process. The first step is the generation of male worms according to the desired method (A). It is advantageous to choose the more easy and recognizable strain for that purpose. Then, favor the crossing by putting hermaphrodites of strain 1 (Y) with males of strain 2 (B). All the F1 will be heterozygous for both transgenes. The third step is to pick males of the F1 and cross them with hermaphrodites of strain 1 (Y) (C). Then, pick hermaphrodites positive for the most recognizable transgene and let them reproduce by self-fertilization. Discard the parental worm and let the progeny to growth. Test random worms for positivity in both transgenes (D). Repeat this procedure until a homogenous population of worms positive for both transgenes is obtained. Figure designed and made with Servier Medical Art.

Figure 2

Different methodological approaches using C. elegans advantages. According to the goal of the experiments, different combinations of approaches could be performed. (A) Combining pharmacological treatment with RNAi-mediated knockdown. (B) Create different crossbreeds between C. elegans reporter strains and/or models of neurodegeneration with RNAi-mediated knockdown. (C) Create different crossbreeds between C. elegans reporter strains and/or models of neurodegeneration with pharmacological treatments. (D) Combined the generation of new crossbreeds with pharmacological and RNAi-mediated knockdown treatments. (E) Different experimental approaches could be tested at the phenotypic level by analyzing worms’ behavior, the distribution of fluorescent proteins by microscopy, protein or RNA levels, or even omics analysis of the genome, transcriptome, proteome, or metabolomic levels. Figure designed and made with Servier Medical Art and NIH BioART.