A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation

Nivedha Mohanraj; Neha S Joshi; Roshni Poulose; Rahul R Patil; Rashmi Santhoshkumar; Anubhav Kumar; Girish P Waghmare; Amit Kumar Saha; Syeda Zehra Haider; Yogananda S Markandeya; Gourav Dey; Laxmi T Rao; Periyasamy Govindaraj; Bhupesh Mehta

doi:10.1016/j.toxrep.2022.07.002

A proteomic study to unveil lead toxicity-induced memory impairments invoked by synaptic dysregulation

Toxicol Rep. 2022 Jul 7:9:1501-1513. doi: 10.1016/j.toxrep.2022.07.002. eCollection 2022.

Authors

Affiliations

¹ Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India.
² Institute of Bioinformatics, Bengaluru, India.
³ Manipal Academy of Higher Education, Manipal, India.
⁴ Electron Microscopy-Common Research Facility, Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India.
⁵ Department of Neurophysiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India.
⁶ Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.

Abstract

Lead (Pb²⁺), a ubiquitously present heavy metal toxin, has various detrimental effects on memory and cognition. However, the molecular processes affected by Pb²⁺ 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 Pb²⁺ exposure induced impairments in spatial cognition. Further, proteomic analysis of synaptosomal fractions revealed differential alteration of 289 proteins, which shows functional significance in elucidating Pb²⁺ induced physiological changes. Focusing on the association of Small Ubiquitin-like MOdifier (SUMO), a post-translational modification, with Pb²⁺ 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 Pb²⁺ 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.

Keywords: Cognitive impairment; Lead toxicity; Memory; Proteomics; SUMO; Synaptosome.