Memories’ Sweet Origins

Little did entertainer Bob Hope know that “thanks for the memory” not only is a moving song lyric but also acknowledges the effect of making changes in sugar molecules on a brain protein.

Researchers have found that O-linked β-N-acetyl-d-glucosamine (O-GlcNAc) discourages memory formation when it’s attached to the transcription factor CREB and that memory improves when it’s removed or absent (Nat. Chem. Biol., DOI: 10.1038/nchembio.770). The finding reveals a previously unknown sugar-based mechanism for regulating gene expression, neural development, and memory. It could lead to new ways to enhance memory or to reduce memory loss among patients with diseases such as Alzheimer’s.

O-GlcNAc modification of proteins was known to influence brain development, neuronal signaling, and neurodegeneration. But how it influences such processes on a molecular level has been uncertain.

Using a sugar-tagging technique they developed, carbohydrate chemist Linda C. Hsieh-Wilson of California Institute of Technology and coworkers have shown for the first time the profound effects of O-GlcNAc on the transcription factor CREB. Working with mice, they found that gene expression, neuronal axon and dendrite growth, and memory formation are reduced by CREB glycosylation with O-GlcNAc and promoted by blocking that glycosylation.

The same three processes are enhanced by CREB phosphorylation and reduced by CREB dephosphorylation. Phosphate and O-GlcNAc appear to work together, albeit in an opposite way.

Together with many prior studies, the work shows “how the fields of neurobiology, transcription, and signaling need to pay attention to this ubiquitous sugar modification of proteins to understand biology at the molecular level,” says O-GlcNAc expert Gerald W. Hart of Johns Hopkins University. “Focusing only on phosphoryation will reveal only part of the story.”

How memories are made “is one of the great biological mysteries,” says another O-GlcNAc specialist, John A. Hanover of the National Institutes of Health. The new findings “provide an important clue” to better understand that process.—Stu Borman