CMT1A gene defect disrupts cells crucial for nerve health, study says

Duplication seen to affect developing Schwann cells that make myelin sheath

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by Steve Bryson, PhD |

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Duplication of the PMP22 gene, the underlying cause of Charcot-Marie-Tooth disease type 1A (CMT1A), disrupts the development of Schwann cells essential to the myelin sheath that protects nerve cells, a study in mouse models and cells derived from patients reports.

Specifically, the gene’s duplication dysregulates fat-like lipid metabolism, storage, and trafficking of the developing cells, the researchers found, suggesting ways of correcting such dysregulation.

“Targeting lipid handling and metabolism could hold promise for the treatment of CMT1A patients,” the scientists wrote.

“Our work provides a foundation for the development of targeted therapies that address the underlying molecular defects in CMT1A,” Ludo Van Den Bosch, PhD, the study’s senior author at the University of Leuven, in Belgium, said in a university news release. “By understanding how PMP22 duplication disrupts lipid homeostasis, we can now explore innovative approaches to restore cellular function and potentially halt the progression of this devastating disease.”

The study, “PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells,” was published in the journal Brain.

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Repairs done by Schwann cells help limit nerve damage in CMT: Study

Myelin sheath that protects nerve fibers is rich in fat-like lipids

Charcot-Marie-Tooth disease is the name give to a group of inherited disorders marked by dysfunction of peripheral nerves, which send signals to and from the brain and spinal cord and the rest of the body.

Among CMT subtypes, CMT1A is the most common form, usually caused by a duplication (an extra copy) of the PMP22 gene. This gene carries instructions for peripheral myelin protein 22, a protein part of the myelin sheath, a layer covering nerve fibers that is rich in fat-like lipids.

Because the myelin sheath helps speed the transmission of nerve signals, PMP22 duplication disrupts proper myelin formation, slowing nerve signals and leading to disease symptoms that include muscle weakness and sensory loss in the extremities.

However, the precise mechanisms by which PMP22 duplication contributes to CMT1A have remained elusive, the scientists noted.

Van Den Bosch and colleagues investigated the role of PMP22 duplication in CMT1A mouse models and CMT patient-derived developing Schwann cells, the type of cell that makes myelin in the peripheral nervous system.

“This myelin sheath electrically insulates the nerves and Schwann cells also provide metabolic support,” said Robert Prior, PhD, the study’s co-first author.

CMT1A defect ’causes abnormal lipid storage and lipid-mediated stress’

An analysis of the sciatic nerve in a CMT1A mouse model found major disruptions in lipid metabolism pathways and cholesterol production. Cholesterol is an essential structural component of cell membranes and a key regulator of membrane fluidity. Notably, cholesterol production was continuously repressed in CMT1A mice.

Further experiments confirmed these findings using a mouse model of less severe CMT1A. Findings here showed dysregulated lipid metabolism in the sciatic nerve, thinner myelin sheaths, and reduced nerve fiber diameter.

Scientists then examined gene activity in Schwann cell precursors derived from CMT1A patients, and found that several genes related to myelin and Schwann cell development were dysregulated. Gene activity related to lipid metabolism and autophagy, an essential process that removes damaged and unnecessary molecules in cells, was strongly suppressed.

CMT1A Schwann cell precursors appeared to have disordered membranes and a significant reduction in free cholesterol levels within the cell membrane. There also was a notable reduction in the mobility of lipid rafts, clusters of lipids that influence membrane fluidity. Under lipid starvation, a delay in the formation of lipid droplets, which function as hubs to coordinate lipid uptake, distribution, storage, and use, was evident.

Lipid droplet formation then was induced in CMT1A Schwann cell precursors. Over time, the number and size of lipid droplets increased significantly in these cells compared with control cells.

This work “strongly indicates that one additional copy of PMP22 causes abnormal lipid storage and lipid-mediated stress,” the researchers wrote.

Selective targeting of lipid pathways might treat CMT1A, work suggests

“One of our key findings was the identification of dysregulated lipids in the plasma membrane of developing human Schwann cells carrying the PMP22 duplication,” Prior noted. “This impairs the structural integrity and bending properties of the plasma [cell] membrane, compromising the ability of the Schwann cells to ‘wrap’ around the peripheral nerves.”

Finally, after exposing CMT1A Schwann cells to a potent stimulator of autophagy and lipid breakdown, the generation of lipid droplets was lower than that of control cells. The number of lysosomes, the cell’s recycling centers that participate in autophagy, also was significantly decreased in treated cells.

Moreover, treating CMT1A Schwann cells with an agent that blocks a receptor of progesterone, a hormone made from cholesterol, rescued the deficit in membrane cholesterol. This implies that “selectively targeting cholesterol release from [lipid droplets] facilitates the incorporation of free cholesterol into the [membrane] of CMT1A [Schwann cells],” the scientists wrote.

“The dysregulation of lipids in the plasma membrane finally allows us to understand why the communication between CMT1A patient Schwann cells and peripheral nerves breaks down, even before the onset of myelination,” Prior added.