Researchers Uncover Key Step In Manufacture Of Memory Protein

The protein is known as mBDNF, which stands for mature brain-derived neurotrophic factor. In an earlier study, another team of NICHD researchers had shown that mBDNF is essential for the formation of long-term memory, the ability to remember things for longer than a day.

“Understanding how BDNF is made may help us to better understand the learning process, perhaps leading to better treatments for disorders of learning and memory,” said Duane Alexander, M.D., Director of the National Institute of Child Health and Human Development.

The research team was led by Y.Peng Loh Ph.D, of NICHD’s Section on Cellular Neurobiology. The researchers published their work in the January 20 issue of Neuron.

Specifically, the researchers discovered that the enzyme carboxypeptidase E, (CPE) is needed to deliver the early, or inactive, form of BDNF — proBDNF — to a special compartment in the neuron (nerve cell.) Once in the compartment, proBDNF is chemically converted into active mBDNF. After mBDNF is formed, it is released to the outside of the neuron, where it binds to receptors on other neurons and stimulates them to form long-term memory.

Dr. Loh explained that, like other proteins, proBDNF is made inside the endoplasmic reticulum, a convoluted network of tubes and channels inside the cell. The proBDNF winds through the endoplasmic reticulum until it reaches another structure within the cell, the golgi apparatus. There, the proBDNF binds to CPE, which protrudes from special rafts of fatty, cholesterol-rich molecules known as lipids. If this binding process does not take place, proBDNF cannot be converted to its active form. Dr. Loh explained that the proBDNF molecule has four projections, resembling prongs. These prongs fit into a corresponding indentation on CPE, analogous to the way a plug for an electric appliance fits into an electric wall outlet, Dr. Loh said.

The golgi apparatus then encases the lipid rafts — along with proBDNF — in bubble-like structures known as vesicles. Within these vesicles, proBDNF is converted to mBDNF by other enzymes. The vesicles are then transported to the cell’s outer membrane, where they remain until they are ready to be secreted. Once the cell receives an electrical signal from another neuron, these vesicles fuse with the cell’s outer membrane, open up, and release mBDNF.

During their research, Dr. Loh and her colleagues observed mice genetically incapable of producing CPE. In these mice, proBDNF could not be delivered into the lipid raft-rich vesicles for conversion to mBDNF. Instead, it appeared to leak out of the golgi apparatus, where it leached through the cell membrane without first having been converted to active mBDNF. Because they cannot make mBDNF, CPE-deficient mice have poor long-term memory.

Dr. Loh added that, in the near future, an understanding of the chemical mechanism she and her colleagues deciphered in the current study may provide insight into long-term memory deficits. She explained that other researchers have learned that some human beings lack normal CPE due to mutations in the CPE gene. Future research may determine if the CPE mutation affects these individuals’ long-term memory.

The NICHD is part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation.