A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation. (2022)

• Record Type: Journal Article
• Authors: Mohanraj, Nivedha; Joshi, Neha S.; Poulose, Roshni; Patil, Rahul R.; Santhoshkumar, Rashmi; Kumar, Anubhav; Waghmare, Girish P.; Saha, Amit Kumar; Haider, Syeda Zehra; Markandeya, Yogananda S.; Dey, Gourav; Rao, Laxmi T.; Govindaraj, Periyasamy; Mehta, Bhupesh
• Is Part Of: Toxicology reports. Volume 9(2022)
• Page Start: 1501
• Page End: 1513
• Publication Date: 2022
• Subjects: Lead toxicity -- Synaptosome -- Memory -- Cognitive impairment -- Proteomics -- SUMO; Toxicology -- Periodicals; Clinical toxicology -- Periodicals; Drug-Related Side Effects and Adverse Reactions; Hazardous Substances; Poisoning; Toxicology; Electronic journals; Periodicals; Periodicals; 571.9505
• DOI: 10.1016/j.toxrep.2022.07.002
• Languages: English
• ISSNs: 2214-7500

Abstract

Abstract: Lead (Pb 2+ ), a ubiquitously present heavy metal toxin, has various detrimental effects on memory and cognition. However, the molecular processes affected by Pb 2+ causing structural and functional anomalies are still unclear. To explore this, we employed behavioral and proteomic approaches using rat pups exposed to lead acetate through maternal lactation from postnatal day 0 (P0) until weaning. Behavioral results from three-month-old rats clearly emphasized the early life Pb 2+ exposure induced impairments in spatial cognition. Further, proteomic analysis of synaptosomal fractions revealed differential alteration of 289 proteins, which shows functional significance in elucidating Pb 2+ induced physiological changes. Focusing on the association of Small Ubiquitin-like MOdifier (SUMO), a post-translational modification, with Pb 2+ induced cognitive abnormalities, we identified 45 key SUMO target proteins. The significant downregulation of SUMO target proteins such as metabotropic glutamate receptor 3 (GRM3), glutamate receptor isoforms 2 and 3 (GRIA 2 and GRIA3) and flotilin-1 (FLOT1) indicates SUMOylation at the synapses could contribute to and drive Pb 2+ induced physiological imbalance. These findings identify SUMOylation as a vital protein modifier with potential roles in hippocampal memory consolidation and regulation of cognition. Data availbility: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD034212&#34. Graphical Abstract: ga1 HIghlights: Early life lead (Pb 2+ ) exposure at 100 ppm in rats impairs memory functions. Lead exposure at 100 ppm causes dysregulation of the hippocampal synaptic proteome. Synaptic SUMOylome could play a major role in Pb 2+ -induced neurodegeneration.