Posts tagged myelination

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.

(Source: cincinnatichildrens.org)

In animal study, inflammation stops cells from accessing iron needed for brain development

Researchers exploring the link between newborn infections and later behavior and movement problems have found that inflammation in the brain keeps cells from accessing iron that they need to perform a critical role in brain development.

Specific cells in the brain need iron to produce the white matter that ensures efficient communication among cells in the central nervous system. White matter refers to white-colored bundles of myelin, a protective coating on the axons that project from the main body of a brain cell.

The scientists induced a mild E. coli infection in 3-day-old mice. This caused a transient inflammatory response in their brains that was resolved within 72 hours. This brain inflammation, though fleeting, interfered with storage and release of iron, temporarily resulting in reduced iron availability in the brain. When the iron was needed most, it was unavailable, researchers say.

“What’s important is that the timing of the inflammation during brain development switches the brain’s gears from development to trying to deal with inflammation,” said Jonathan Godbout, associate professor of neuroscience at The Ohio State University and senior author of the study. “The consequence of that is this abnormal iron storage by neurons that limits access of iron to the rest of the brain.”

The research is published in the Oct. 9, 2013, issue of The Journal of Neuroscience.

The cells that need iron during this critical period of development are called oligodendrocytes, which produce myelin and wrap it around axons. In the current study, neonatal infection caused neurons to increase their storage of iron, which deprived iron from oligodendrocytes.

In other mice, the scientists confirmed that neonatal E. coli infection was associated with motor coordination problems and hyperactivity two months later – the equivalent to young adulthood in humans. The brains of these same mice contained lower levels of myelin and fewer oligodendrocytes, suggesting that brief reductions in brain-iron availability during early development have long-lasting effects on brain myelination. 

The timing of infection in newborn mice generally coincides with the late stages of the third trimester of pregnancy in humans. The myelination process begins during fetal development and continues after birth.

Though other researchers have observed links between newborn infections and effects on myelin and behavior, scientists had not figured out why those associations exist. Godbout’s group focuses on understanding how immune system activation can trigger unexpected interactions between the central nervous system and other parts of the body.

“We’re not the first to show early inflammatory events can change the brain and behavior, but we’re the first to propose a detailed mechanism connecting neonatal inflammation to physiological changes in the central nervous system,” said Daniel McKim, a lead author on the paper and a student in Ohio State’s Neuroscience Graduate Studies Program.

The neonatal infection caused several changes in brain physiology. For example, infected mice had increased inflammatory markers, altered neuronal iron storage, and reduced oligodendrocytes and myelin in their brains. Importantly, the impairments in brain myelination corresponded with behavioral and motor impairments two months after infection.

Though it’s unknown if these movement problems would last a lifetime, McKim noted that “since these impairments lasted into what would be young adulthood in humans, it seems likely to be relatively permanent.”

The reduced myelination linked to movement and behavior issues in this study has also been associated with schizophrenia and autism spectrum disorders in previous work by other scientists, said Godbout, also an investigator in Ohio State’s Institute for Behavioral Medicine Research (IBMR).

“More research in this area could confirm that human behavioral complications can arise from inflammation changing the myelin pattern. Schizophrenia and autism disorders are part of that,” he said.

This current study did not identify potential interventions to prevent these effects of early-life infection. Godbout and colleagues theorize that maternal nutrition – a diet high in antioxidants, for example – might help lower the inflammation in the brain that follows a neonatal infection.

“The prenatal and neonatal period is such an active time of development,” Godbout said. “That’s really the key – these inflammatory challenges during critical points in development seem to have profound effects. We might just want to think more about that clinically.”

Testosterone and its derivatives could constitute an efficient treatment against myelin diseases such as multiple sclerosis, reveals a study by researchers from the Laboratoire d’Imagerie et de Neurosciences Cognitives (CNRS/Université de Strasbourg), in collaboration in particular with the “Neuroprotection et Neurorégénération: Molécules Neuroactives de Petite Taille” unit (Inserm/Université Paris-Sud). Myelin composes the sheaths that protect the nerve fibers and allow the speed of nerve impulses to be increased. A deficit in the production of myelin or its destruction cause serious illnesses for which there is no curative treatment. The researchers have shown that in mice brains whose nerve fibers have been demyelinated, testosterone and a synthetic analog induce the regeneration of oligodendrocytes, the cells responsible for myelination, and that they stimulate remyelination. This work is published on January in the journal Brain.

(Source)