UNEXPECTED CLUE TO PERIPHERAL NEUROPATHIES FOUND
New research shows
that disrupting the molecular function of a tumor suppressor causes improper
formation of a protective insulating sheath on peripheral nerves -- leading to
neuropathy and muscle wasting in mice similar to that in human diabetes and
neurodegeneration
Scientists from
Cincinnati Children's Hospital Medical Center report their findings online
Sept. 26 in Nature Communications.
The study suggests that normal molecular function of the tumor suppressor gene
Lkb1 is essential to an important metabolic transition in cells as peripheral
nerves (called axons) are coated with the protective myelin sheath by Schwann
glia cells.
"This study is
just the tip of the iceberg and a fundamental discovery because of the
unexpected finding that a well-known tumor suppressor gene has a novel and
important role in myelinating glial cells," said Biplab Dasgupta PhD,
principal investigator and a researcher at the Cincinnati Children's Cancer and
Blood Diseases Institute (CBDI). "Additional study is needed, as the
function of Lkb1 may have broader implications -- not only in normal
development, but also in metabolic reprogramming in human pathologies. This
includes functional regeneration of axons after injury and demyelinating
neuropathies."
The process of
myelin sheath formation (called myelination) requires extraordinarily high
levels of lipid (fat) synthesis because most of myelin is composed of lipids,
according to Dasgupta. Lipids are made from citric acid which is produced in
the powerhouse of cells called mitochondria. Success of this sheathing process
depends on the cells shifting from a glycolytic to mitochondrial oxidative
metabolism that generates citric acid, the authors report.
Dasgupta's research
team used Lkb1 mutant mice in the current study. Because the mice did not
express Lkb1 in myelin forming glial cells, this allowed scientists to analyze
its role in glial cell metabolism and formation of the myelin sheath coating.
When the function of
Lkb1 was disrupted in laboratory mice, it blocked the metabolic shift from
glycolytic to mitochondrial metabolism, resulting in a thinner myelin sheath
(hypomyelination) of the nerves. This caused muscle atrophy, hind limb
dysfunction, peripheral neuropathy and even premature death of these mice,
according to the authors.
Peripheral
neuropathy involves damage to the peripheral nervous system -- which transmits
information from the brain and spinal cord (the central nervous system) to
other parts of the body, according to the National Institute of Neurological
Disorders and Stroke (NINDS). There are more than 100 types of peripheral
neuropathy, and damage to the peripheral nervous system interferes with crucial
messages from the brain to the rest of the body.
The scientists also
reported that reducing Lkb1 in Schwann cells decreased the activity of critical
metabolic enzyme citrate synthase that makes citric acid. Enhancing Lkb1
increased this activity.
They tested the
effect of boosting citric acid levels in the Lbk1 mutant Schwann cells. This
enhanced lipid production and partially reversed myelin sheath formation
defects in Lbk1 mutant Schwann cells. Dasgupta said this further underscores
the importance of Lbk1 and the production of citrate synthase.
Dasgupta and his
colleagues are currently testing whether increasing the fat content in the Lbk1
mutant mice diet improves hypomyelination defects. The researchers emphasized
the importance of additional research into the laboratory findings to extend
their relevance more directly to human disease.
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