Researchers at the University of Iowa (UI) have identified a novel protein folding mechanism in the endoplasmic reticulum (ER) that is essential for long-term memory storage and has linked this mechanism to cognitive deficits in mouse models of Alzheimer’s disease and related dementias.

The findings are published in the journal Science Advances in a paper titled, “Endoplasmic reticulum chaperone genes encode effectors of long-term memory,” and the study was led by Snehajyoti Chatterjee, PhD, a research associate in the lab of Ted Abel, PhD, director of the Iowa Neuroscience Institute and chair and DEO of the UI department of neuroscience and pharmacology.

“The mechanisms underlying memory loss associated with Alzheimer’s disease and related dementias (ADRD) remain unclear, and no effective treatments exist,” the researchers wrote. “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.”

“The role of protein folding machinery in long-term memory has been overlooked for decades,” Chatterjee said. “We know that gene expression and protein synthesis are essential for long-term memory consolidation and following learning a large number of proteins are synthesized. For proteins to be functionally active they need to be folded correctly. Our work demonstrates the conceptual idea that these chaperone proteins are the ones that actually fold the proteins to impact synaptic function and plasticity.”

The team also used gene therapy to reactivate the chaperone protein in a mouse model and found that the memory deficit was reversed, confirming that the protein folding machinery acts as a molecular switch for memory.

“Identifying this protein folding mechanism is a crucial step toward understanding how memories are stored and what goes wrong in diseases associated with memory impairment,” Abel said. “Even though we are not yet at a point of translating this to patient care, understanding this pathway is essential to one day being able to prevent and treat neurodegenerative disease.”

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