Endoplasmic reticulum chaperone genes encode effectors of long-term memory
Snehajyoti Chatterjee, Ethan Bahl, Utsav Mukherjee, Emily N. Walsh, Mahesh Shivarama Shetty, Amy L. Yan, Yann Vanrobaeys, Joseph D. Lederman, Karl-Peter Giese, Jacob J. Michaelson, Ted Abel
Abstract
The mechanisms underlying memory loss associated with Alzheimer's disease and related dementias (ADRD) remain unclear, and no effective treatments exist. Fundamental studies have shown that a set of transcriptional regulatory proteins of the nuclear receptor 4a (Nr4a) family serve as molecular switches for long-term memory. Here, we show that Nr4a proteins regulate the transcription of genes encoding chaperones that localize to the endoplasmic reticulum (ER). These chaperones fold and traffic plasticity-related proteins to the cell surface during long-lasting forms of synaptic plasticity and memory. Dysregulation of Nr4a transcription factors and ER chaperones is linked to ADRD, and overexpressing Nr4a1 or the chaperone Hspa5 ameliorates long-term memory deficits in a tau-based mouse model of ADRD, pointing toward innovative therapeutic approaches for treating memory loss. Our findings establish a unique molecular concept underlying long-term memory and provide insights into the mechanistic basis of cognitive deficits in dementia.