Elucidation of the Molecular Mechanisms Underlying the Ability of C. Elegans Pharynx to Recognize as Toxicant the Soluble, Pre-Fibrillar Assemblies of the Amyloidogenic Proteins

Romeo, Margherita (2019). Elucidation of the Molecular Mechanisms Underlying the Ability of C. Elegans Pharynx to Recognize as Toxicant the Soluble, Pre-Fibrillar Assemblies of the Amyloidogenic Proteins. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000e614

Abstract

Immunoglobulin light chain amyloidosis (AL) is the most common form of systemic amyloidosis in which a plasma-cell dyscrasia results in the overproduction of amyloidogenic immunoglobulin light chains (LC). Although LC organize in extracellular deposits in different target organs, approximately 75% of patients manifest heart involvement at presentation, with a median survival of only 6 months if chemotherapy fails to stop LC production. Although an active role of radical oxygen species (ROS) has already been envisaged, the actual mechanisms behind their generation remain elusive.

In this study, it was observed that amyloidogenic LC purified from patients with cardiac involvement intrinsically generated high levels of ROS and, when administered to C. elegans resulted in ROS production. These species can directly target the pharyngeal cells, causing remarkable damage particularly at the mitochondrial level, similar to that observed in amyloid-affected hearts from AL patients. Tetracycline counteracted all these ROS-mediated effects and, when added to standard chemotherapy, they reduced early deaths in patients with cardiac AL. To limit and repair the stress-induced damage, different intracellular signalling events are activated. In particular, the nuclear translocation of the FOXO/DAF-16 transcription factor triggers the transcription of stress-responsive genes, including heat-shock protein (hsp)-16.2 and manganese superoxide dismutase (sod)-3, and controlling stress resistance and survival.

All these effects were entirely dependent on the presence of metal ions, particularly copper. Metal chelators or metal-binding compounds, particularly the new drug PBT2, block ROS production and interrupt the vicious cycle of oxidative stress. In C. elegans, low doses of PBT2 in combination with tetracycline result in a synergistic beneficial effect, highlighting the potential application of this pharmacological strategy for AL patients. These findings indicate that metal-induced oxidative stress, already reported to be linked with some neurological disorders, is also a key element in cardiac AL amyloidosis.

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