As a graduate student, Linda Hsieh-Wilson is remembered as having accomplished the equivalent of three Ph.D. theses in the span of time it usually takes to finish one. Now, as a young investigator, she is bringing her chemist's training—and indefatigable curiosity—to neurobiology. Instead of concentrating exclusively on the "big picture," as some neurobiologists often do, Hsieh-Wilson is focusing on a less well-studied—but perhaps even more important—area: How does the right chemistry keep the brain working properly?

To be more specific, she is integrating organic chemistry with neurobiology to understand how key carbohydrates, and their various derivatives, alter the structure and function of proteins in the brain. This is an area of biology that has largely been avoided by researchers because of the dearth of experimental approaches that can be used to study these important biopolymers.

Hsieh-Wilson aims to change that by inventing new chemical tools to probe protein glycosylation, a process that is critical for cellular communication, and, within the realm of neurobiology, may be important for learning, memory, and motor control.

Many cellular proteins—including nuclear pores, oncogenes, cytoskeletal proteins, heat shock proteins, and viral and transcription regulatory proteins—contain amino acid building blocks that chemically bond to a particular sugar, called N-acetylglucosamine (GlcNAc). This bonding process is known as O-GlcNAc glycosylation. Researchers have long suspected that GlcNAc is important to neurons, and it has been implicated in diabetes, Alzheimer's disease, and cancer. But the precise chemistry involved has remained elusive.

To learn more about glycosylation, Hsieh-Wilson has borrowed and enhanced techniques used to study another common protein modification, protein phosphorylation. Her lab has identified and mapped several novel proteins bearing the GlcNAc modification, including a critical transcription factor, CREB, which regulates many cellular processes.

More broadly, Hsieh-Wilson's team also has screened the entire mammalian brain for all O-GlcNAc-glycosylated proteins, using a new process that her laboratory developed. This proteomics effort netted 23 new, and many known, proteins bearing the GlcNAc modificationincluding those involved in regulating processes such as drug addiction, hormone receptor activation, and memory consolidation. The Hsieh-Wilson lab is now studying several of these new proteins to learn what functions O-GlcNAc glycosylation might encode.