Speaker: Vijendra Sharma
Title: Translation Control Mechanisms in the Brain
Date/Time: 5 May 2021 / 13:40 - 14:30
Abstract: Learning, memory, and perception rely on an intricate network of proteins that orchestrate higher cognitive functions of the brain. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories. Eukaryotic cells respond to diverse stress stimuli by activating the integrated stress response (ISR) pathway, which phosphorylates the alpha (α) subunit of eukaryotic initiation factor 2 (peIF2α) and inhibits general protein synthesis but stimulates the translation of specific mRNAs with upstream open reading frames in their 5′UTRs to cope with the stress. Conversely, the genetic and pharmacological inhibition of ISR kinases or mimicking reduced p-eIF2α with the ISR inhibitor ISRIB or mutating the eIF2α phosphorylation site (serine 51) enhances long-term memory. I have used advanced genetic mouse models of eIF2, combined with gene discovery studies, to dissect the cell-types-specific circuits by which the ISR pathway gates cognitive processing in the brain. The results delineate a mechanism for cognitive dysfunction and position eIF2 as a promising therapeutic target in brain disorders with memory impairment such as neurodegenerative diseases.
Bio: Dr. Vijendra Sharma is a Research Associate in the Department of Biochemistry and Goodman Cancer Research Centre at McGill University, Canada. His research interests cover several aspects of mRNA translation and translational control mechanisms in different cell types, leading to many high-quality publications. He has recently published a paper (Sharma et al., Nature, 2020), which describes a new mechanism of memory formation via eIF2a phosphorylation-dependent translational control in somatostatin-positive neurons. He has also used state-of-the-art cell-type-specific approaches and showed that the upregulation of the mTORC1/4E-BP2-dependent translation in parvalbumin interneurons, but not in other cell types, increases susceptibility to seizures (Sharma et al., 2021, PNAS). He has been awarded several prestigious fellowships, including VATAT Postdoctoral Fellowship and International Israel Government Scholarship. Additionally, Dr. Sharma is a co-inventor on a patent, which utilizes a gene therapy-based approach to treat aging and Alzheimer’s disease-associated cognitive dysfunction by targeting translation in the brain.