article
Researchers discover gene crucial for nerve cell insulation
Contact: Robert Bock
bockr@mail.nih.gov
301-496-5133
NIH/National Institute of Child Health and Human Development
Researchers funded by the National Institutes of Health have
discovered how a defect in a single master gene disrupts the process
by which several genes interact to create myelin, a fatty coating that
covers nerve cells and increases the speed and reliability of their
electrical signals.
The discovery has implications for understanding disorders of myelin
production. These disorders can affect the peripheral nervous system-
the nerves outside the brain and spine. These disorders are known
collectively as peripheral neuropathies. Peripheral neuropathies can
result in numbness, weakness, pain, and impaired movement. They
include one of the most common genetically inherited disorders,
Charcot-Marie-Tooth disease, which causes progressive muscle
weakening.
The myelin sheath that surrounds a nerve cell is analogous to the
insulating material that coats an electrical cord or wire, keeping
nerve impulses from dissipating, allowing them to travel farther and
faster along the length of the nerve cell.
The researchers discovered how a defect in just one copy of the gene,
known as early growth response gene 2 (EGR2) affects the normal copy
of the gene as well as the functioning of other genes, resulting in
peripheral neuropathy.
"The researchers have deciphered a key sequence essential to the
assembly of myelin," said Duane Alexander, M.D., Director of the
NICHD, the NIH institute that funded the study. "Their discovery will
provide important insight into the origins of disorders affecting
myelin production."
The study appears in the online version of Molecular and Cellular
Biology.
John Svaren, Ph.D., an associate professor in the Department of
Comparative Bioscience at the University of Wisconsin-Madison's School
of Veterinary Medicine, worked with colleagues Scott E. LeBlanc, and
Rebecca M. Ward, to conduct the study. Dr. Svaren is an affiliate of
NICHD-funded mental retardation and developmental disabilities
research center at the Waisman Center at the University of Wisconsin.
Until this discovery, researchers did not fully understand the complex
genetic process that enables Schwann cells, found in the peripheral
nervous system, to coat nerves with myelin.
The Newly Discovered Role of EGR2
During this study, the scientists found that EGR2 produces a protein
that activates several other genes necessary for myelin production.
Some of these genes contain the information needed to make peripheral
myelin protein 22 (PMP-22) and myelin protein zero (MPZ). MPZ is the
most abundant protein in myelin in the peripheral nervous system.
The overproduction or underproduction of the proteins PMP22 and MPZ
account for the majority of inherited peripheral neuropathies, Dr.
Svaren said.
Ultimately, the sequence of activating genes "switches on" the Schwann
cell, which wraps the nerve axon, the arm-like projection that conveys
nerve impulses, in a myelin sheath.
The scientists' research also resolved a long-standing mystery
surrounding why a single mutant copy of the EGR2 gene disrupts the
functioning of the normal EGR2 gene, leading to a disorder of the
nervous system.
In many genetic conditions, the unaffected copy of an affected gene
continues to produce its protein. However, the researchers found that
the mutant EGR2 copy interferes with the interaction between the
normal EGR2 gene and another myelin gene, SOX10, as the two try to
work together to produce the myelin protein MPZ.
Therapeutic Potential
By understanding the process which creates myelin, researchers may now
be able to investigate new therapies for disorders affecting myelin.
"Our research has uncovered a whole new mechanism for regulating
myelin genes," said Dr. Svaren. "Our hope is to exploit this knowledge
so that we can adjust the levels of myelin genes such as PMP22 and
MPZ, and thereby create an effective treatment for myelin diseases."
Understanding the process by which nerve cells are myelinated also
could be applied to other disorders as well, Dr. Svaren said. Diabetic
neuropathy, which results in a loss of feeling in the extremities,
also is thought to involve myelin production.
Dr. Svaren added that it is possible that the current study's findings
about myelin production in the peripheral nervous system could lead to
greater understanding of how myelination takes place in the central
nervous system (the brain and spinal cord). Myelination in the central
nervous system is not well understood. Multiple sclerosis, a
degenerative muscular disorder that can be fatal, results from the
destruction of myelin in the central nervous system.
Contact: Robert Bock
bockr@mail.nih.gov
301-496-5133
NIH/National Institute of Child Health and Human Development
Researchers funded by the National Institutes of Health have
discovered how a defect in a single master gene disrupts the process
by which several genes interact to create myelin, a fatty coating that
covers nerve cells and increases the speed and reliability of their
electrical signals.
The discovery has implications for understanding disorders of myelin
production. These disorders can affect the peripheral nervous system-
the nerves outside the brain and spine. These disorders are known
collectively as peripheral neuropathies. Peripheral neuropathies can
result in numbness, weakness, pain, and impaired movement. They
include one of the most common genetically inherited disorders,
Charcot-Marie-Tooth disease, which causes progressive muscle
weakening.
The myelin sheath that surrounds a nerve cell is analogous to the
insulating material that coats an electrical cord or wire, keeping
nerve impulses from dissipating, allowing them to travel farther and
faster along the length of the nerve cell.
The researchers discovered how a defect in just one copy of the gene,
known as early growth response gene 2 (EGR2) affects the normal copy
of the gene as well as the functioning of other genes, resulting in
peripheral neuropathy.
"The researchers have deciphered a key sequence essential to the
assembly of myelin," said Duane Alexander, M.D., Director of the
NICHD, the NIH institute that funded the study. "Their discovery will
provide important insight into the origins of disorders affecting
myelin production."
The study appears in the online version of Molecular and Cellular
Biology.
John Svaren, Ph.D., an associate professor in the Department of
Comparative Bioscience at the University of Wisconsin-Madison's School
of Veterinary Medicine, worked with colleagues Scott E. LeBlanc, and
Rebecca M. Ward, to conduct the study. Dr. Svaren is an affiliate of
NICHD-funded mental retardation and developmental disabilities
research center at the Waisman Center at the University of Wisconsin.
Until this discovery, researchers did not fully understand the complex
genetic process that enables Schwann cells, found in the peripheral
nervous system, to coat nerves with myelin.
The Newly Discovered Role of EGR2
During this study, the scientists found that EGR2 produces a protein
that activates several other genes necessary for myelin production.
Some of these genes contain the information needed to make peripheral
myelin protein 22 (PMP-22) and myelin protein zero (MPZ). MPZ is the
most abundant protein in myelin in the peripheral nervous system.
The overproduction or underproduction of the proteins PMP22 and MPZ
account for the majority of inherited peripheral neuropathies, Dr.
Svaren said.
Ultimately, the sequence of activating genes "switches on" the Schwann
cell, which wraps the nerve axon, the arm-like projection that conveys
nerve impulses, in a myelin sheath.
The scientists' research also resolved a long-standing mystery
surrounding why a single mutant copy of the EGR2 gene disrupts the
functioning of the normal EGR2 gene, leading to a disorder of the
nervous system.
In many genetic conditions, the unaffected copy of an affected gene
continues to produce its protein. However, the researchers found that
the mutant EGR2 copy interferes with the interaction between the
normal EGR2 gene and another myelin gene, SOX10, as the two try to
work together to produce the myelin protein MPZ.
Therapeutic Potential
By understanding the process which creates myelin, researchers may now
be able to investigate new therapies for disorders affecting myelin.
"Our research has uncovered a whole new mechanism for regulating
myelin genes," said Dr. Svaren. "Our hope is to exploit this knowledge
so that we can adjust the levels of myelin genes such as PMP22 and
MPZ, and thereby create an effective treatment for myelin diseases."
Understanding the process by which nerve cells are myelinated also
could be applied to other disorders as well, Dr. Svaren said. Diabetic
neuropathy, which results in a loss of feeling in the extremities,
also is thought to involve myelin production.
Dr. Svaren added that it is possible that the current study's findings
about myelin production in the peripheral nervous system could lead to
greater understanding of how myelination takes place in the central
nervous system (the brain and spinal cord). Myelination in the central
nervous system is not well understood. Multiple sclerosis, a
degenerative muscular disorder that can be fatal, results from the
destruction of myelin in the central nervous system.