Advancing the study of amyloidosis: new insights from omics approaches applied to novel Caenorhabditis Elegans models

The molecular characterization of diseases plays a central role in the rapid advance of modern medicine towards the integration of translational and precision medicine. Insights gained from patient-derived data are first tested and refined in in vitro and in vivo models and, then translated back into clinical practice. In this context, the availability of animal models, along with advancements in cutting-edge technologies like omics sciences, provides a comprehensive and detailed understanding of disease mechanisms, enabling validation of hypotheses and investigation of new therapeutic approaches. The acquisition of high-throughput molecular data on living systems that closely mimic human diseases has proven to be particularly useful in studying amyloidosis, a condition caused by the formation of extracellular deposits or intracellular inclusions of fibrillar protein aggregates. Amyloid deposition is implicated in the pathogenesis of many human diseases with significant social and medical impact. Caenorhabditis elegans (C. elegans) animal models and multi-omics methodologies have been applied to unveil new insights into β2-microglobulin (β2-m) and amyloid β peptide (Aβ) amyloidosis. Transgenic strains of C. elegans expressing high concentrations of WT or low levels of D76N β2-m were used as models of dialysis-related amyloidosis and hereditary form of disease respectively. It has been evaluated how the proteotoxicity of the WT and D76N variants of β2-m can modulate disease pathogenesis in different ways. Both models have been found to exhibit pathological phenotypes with a significant remodeling of proteome and metabolome profiles. Specific altered metabolic pathways were identified and a higher proteotoxicity has been linked to higher levels of WT β2-m. Furthermore, the molecular characterization through omics sciences applied to C. elegans models has proven to be a highly valuable tool for toxicological studies. Considering one of the fundamental principles of precision medicine, which highlights that each individual’s unique genetic profile, environment, and lifestyle contribute to health and disease, susceptibility to toxic agents across different populations has been assessed. The versatility of C. elegans models has been useful to evaluate the effect of external toxic agents, such as persistent environmental pollutants like atrazine, in the presence of amyloid-related conditions, particularly those involving Aβ peptide. This chemical, a widely used herbicide, has been banned in several countries, including Italy, due to its well-documented toxicity, particularly its impact on the endocrine system. Nevertheless, its high persistence in the environment continues to be a significant concern. The impact of the pollutant on a vulnerable population has been observed, and the main metabolic pathways involved were identified. The used approach has been demonstrated to be valuable in addressing the emerging gap regarding the impact of exogenous agents on the health of different populations.