Toxicogenomics for understanding the evolutionary neurotoxicology of manganese

• Grant number: 19/27840-5
• Support type: Regular Research Grants
• Duration: June 01, 2020 - May 31, 2022
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Raúl Bonne Hernández
• Grantee: Raúl Bonne Hernández
• Home Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil

Abstract

Manganese (Mn) is the twelfth most abundant element in the earth's crust. Mn is an essential trace mineral in nutrition that can be neurotoxic and neurodegenerative via environmental and/or nutritional acute and chronic exposure, especially during stages of development. Studies from our group, applying "omics" approaches, have revealed that environmentally relevant concentrations of Mn2+ (0.001-1.5 mM) disrupt protein metabolism, including translation, post-translation and protein degradation, as well as associated pathways such as those involved in energetics, cell signalling, cell cycle and neurotransmitter metabolism, in a suite of organisms, from yeast to human. Notably, these events during or after protein biosynthesis, have been associated with neurodegenerative disorders such as Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease and Huntington's disease. These findings suggest that disruption of protein biosynthesis is a key mechanism for Mn-induced neurotoxicity and neurodegeneration; but sometimes involving different genes or proteins as it is well known that from yeast to human, large and small ribosomal subunits exhibits differences in nucleotide composition. Hence, the evolution stage of organisms needs to be considered before drawing comparisons to humans. Therefore, we propose to develop a phylogenetic analysis of Mn-induced neurotoxicity and neurodegeneration, based on operating metabolic pathways, as to investigate the influence of Mn on the regulation of protein translation. Protein translation is a complex, highly conserved and coordinated process in protein biosynthesis that is mediated by a universal ribonucleoprotein (RNP) complex, the ribosome; and their origin and evolution is central to understanding of cellular processes. Toward this end, we will develop studies with the following biological models spanning several phyla: Saccharomyces cerevisiae (yeast), Caenorhabditis elegans (C. elegans), Danio rerio (zebrafish), and in vitro mammalian systems comprising primary cerebellar granule neurons and primary striatal neurons. In addition, we will employ adverse outcome pathways (AOPs) analysis; a clear-cut mechanistic representation of critical toxicological effects that span levels of biological organization. AOPs share a common structure consisting of a molecular initiating event (MIE), a series of intermediate steps and key events, and an adverse outcome (AO). These "AOs" can be analyzed using a systems biology approach that seeks to explain the properties and behaviour of complex biological systems in terms of their components and their interactions. In addition, this highly innovative and comparative approach will impart improved understanding of, not only on the primary molecular mechanisms of Mn neurotoxicity, but also on its effects on neurodegeneration in higher mammals. Consequently; it could open a new avenue to discovery more precise neurotherapies against Mn toxicity. Lastly, this project also provides an excellent opportunity initiate an international and innovative research network seeking solutions for global environmental-neurological issues with ample opportunities for exchange between universities and funding as well. (AU)