Researchers Uncover Key Step In Manufacture of Memory Protein
A cellular enzyme appears to play a crucial role in the manufacture of a protein
needed for long-term memory, according to a team of researchers led by scientists
at the National Institute of Child Health and Human Development of the National
Institutes of Health.
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
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
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
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.