Gene that suppresses tumor growth also plays a role in forming myelin in the
Dr. Biplab Dasgupta and his team will explore other uses for the tumor-suppressing Lkb1 gene.
A research team in the Cancer and Blood Diseases Institute led by Biplab Dasgupta, PhD, found that the tumor suppressor gene Lkb1 helps to myelinate neurons. Disrupting the gene’s function causes improper formation of myelin sheath, the coating that protects the neuron and helps conduct electrical signals in nerves. This defect in myelin formation leads to neuropathy in the peripheral nervous system and muscle wasting in mice similar to that found in human diabetic neuropathy and other neurodegenerative conditions. Dasgupta and his team reported their findings Sept. 26, 2014, in Nature Communications.
“The finding is unexpected because disruption of this tumor suppressor gene blocked a pathway that is essential for cell proliferation,” says Dasgupta, the study’s principal investigator. “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.”
Formation of the myelin sheath by Schwann cells requires high levels of lipid (fat) synthesis because myelin is mostly composed of lipids, says Dasgupta. Lipids are made from citric acid produced in the cells’ mitochondria. Success of myelin sheath formation relies on the ability of Schwann cells to switch to Lkb1-dependent mitochondrial metabolism to generate more citric acid, the authors report.
The researchers used mice in which Lkb1 was deleted in the myelinating cells. This allowed them to analyze the gene’s role in Schwann cell metabolism and myelin sheath formation.
Deletion of Lkb1 in the mice resulted in a thinner myelin sheath on the nerves and caused muscle atrophy, hind limb dysfunction, peripheral neuropathy and even premature death.
Dasgupta and his colleagues are currently testing whether increasing the fat content in the diet of these mutant mice would improve myelination defects. They will pursue additional research to extend the relevance of their findings to human diseases like diabetic neuropathy.