Amyotrophic Lateral Sclerosis Mechanism: Insights from the Caenorhabditis elegans Models

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a debilitating neurodegenerative condition characterized by the progressive degeneration of motor neurons. Despite extensive research in various model animals, the cellular signal mechanisms of ALS remain elusive, impeding the development of efficacious treatments. Among these models, a well-characterized and diminutive organism, Caenorhabditis elegans (C. elegans), has emerged as a potent tool for investigating the molecular and cellular dimensions of ALS pathogenesis. This review summarizes the contributions of C. elegans models to our comprehension of ALS, emphasizing pivotal findings pertaining to genetics, protein aggregation, cellular pathways, and potential therapeutic strategies. We analyze both the merits and constraints of the C. elegans system in the realm of ALS research and point towards future investigations that could bridge the chasm between C. elegans foundational discoveries and clinical applications.

Keywords: ALS; C. elegans model; cellular mechanism; therapeutic application.

Figure 1

Selective autophagy under physiological and ALS pathological conditions. Protein aggregates, stress granules, and dysfunctional mitochondria serve as substrates for selective autophagy degradation. In physiological conditions (upper panel), these substrates are bound by selective autophagy receptors, such as SQSTM-1/p62 (represented in blue circle), via ubiquitin-binding domains (ubiquitin, in pentagon). The selective autophagy receptors associate with LC3-II proteins in the autophagosome (represented in yellow) or other members of the autophagy machinery. Posttranslational modifications in the receptors can enhance binding with ubiquitinated substrates or the LC3-II protein. TBK1 is one of the main kinases acting in this process. The cargo-receptor- LC3-II complexes are then sequestered by de novo double-membrane vesicles called the autophagosome, which fuses with the lysosome for the final degradation. Under ALS conditions (lower panel), failure in selective autophagy can occur through mutations in the genes encoding the receptors themselves or in the kinase, reducing the activity of the pathway and promoting the accumulation of toxic substrates for motor neurons. Figure was generated by PowerPoint 2013.