Early myelin protein loss may precede nerve fiber damage in Huntington’s

An early and progressive loss of a protein that helps maintain myelin, or the protective sheath around nerve fibers, may contribute to white matter damage in Huntington’s disease, a study suggests.

In a mouse model of Huntington’s, levels of the myelin-associated glycoprotein (MAG) began falling before the loss of other myelin-related proteins and before broader damage to white matter — brain tissue that contains many nerve fibers — including myelin breakdown and nerve fiber degeneration. MAG was also reduced in postmortem brain tissue from people with Huntington’s.

“Our study suggests that white matter decay in HD [Huntington’s disease] brains involves an early progressive loss of MAG in myelin membranes,” the researchers wrote.

The study, “Early reduction of myelin-associated glycoprotein at myelin membranes in Huntington’s disease,” was published in the journal Experimental Neurology.

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Mutant huntingtin protein drives Huntington’s disease

Huntington’s is caused by a mutation in the HTT gene, resulting in the production of an abnormal huntingtin protein that is prone to forming toxic clumps in brain cells.

The disease is marked by the progressive loss of nerve cells and shrinkage of gray matter — brain tissue made up largely of nerve cell bodies — particularly in a brain region called the striatum, which controls voluntary movement and other functions.

Imaging studies also show that white matter, which contains the long nerve fibers connecting different brain regions, can begin deteriorating years before Huntington’s symptoms appear.

Many of these nerve fibers, or axons, are wrapped in myelin, a fatty protective coating that allows fast transmission of electrical signals. Myelin is produced by cells called oligodendrocytes, which also help maintain and repair it throughout life.

Previous research has shown deficits in myelin formation in brains of deceased Huntington’s patients and impaired oligodendrocyte maturation in both patients and mouse models. Data from animal models also suggest that white matter degeneration precedes nerve cell death in Huntington’s.

“Collectively, these lines of evidence suggest that the degradation of the brain white matter is an active contributor to disease progression in HD,” the researchers wrote. “However, the mechanisms by which the HD mutation drives the white matter degeneration remain poorly defined.”

Researchers examine white matter damage in mice

Here, a team of researchers in the U.S. set out to examine white matter damage and how it might be related to changes in myelin proteins in a Huntington’s mouse model.

Among the myelin proteins evaluated, MAG showed an early and progressive decline in the striatum. MAG normally sits in the innermost layer of myelin next to nerve fibers and helps maintain the close interaction between myelin and axons.

Initial experiments showed that MAG’s distribution in oligodendrocytes was markedly altered in the brains of Huntington’s mice. In healthy mice, most MAG was found in fiber bundles containing myelinated axons. In Huntington’s mice, however, MAG labeling was reduced in these bundles and accumulated in the cell bodies of certain oligodendrocytes.

Huntington’s and healthy mice had similar numbers of myelinated axons, but Huntington’s mice had significantly fewer MAG signals in the myelin surrounding the axons.

This suggested that MAG loss was not simply a consequence of complete myelin breakdown and that “the delivery of MAG from its compartments in the [cell bodies] to myelin membranes is impeded in HD mouse brains,” the team wrote.

Following the mice over time, the researchers found that MAG levels in both the striatum and cerebral cortex — the brain’s outer layer — were normal at 1.5 months, but began declining by 3 months and continued to fall with age. Importantly, MAG loss occurred before reductions in several other proteins found in the outer layers of the myelin sheath.

Additional experiments showed that the oligodendrocytes in which MAG was accumulating were newly generated cells. The overall frequency of new oligodendrocytes was similar in Huntington’s and healthy mice. However, a larger proportion of the new cells in Huntington’s mice had not yet acquired MAG, consistent with delayed or impaired maturation.

MAG transport appears disrupted in oligodendrocytes

The team also found that oligodendrocytes from Huntington’s mice had significantly fewer small MAG-containing vesicles — structures that help transport material within cells — and a higher frequency of large MAG-containing structures near the nucleus, where the cell’s DNA is stored.

The findings further support an impaired ability to move MAG out of the compartments surrounding the nucleus and deliver it to myelin membranes in diseased oligodendrocytes.

The researchers proposed that mutant huntingtin may interfere with this transport process. Over time, too little MAG at the myelin membrane could contribute to both myelin breakdown and insufficient myelin repair.

Finally, the team found that MAG and other myelin proteins were reduced in caudate tissue from two deceased Huntington’s patients compared with two healthy controls. In a separate analysis of cerebral cortex tissue from 10 symptomatic Huntington’s patients and five controls, MAG was significantly reduced.

Overall, these findings suggest that “an early progressive loss of MAG in myelin-forming processes is a critical contributor to white matter [damage]” in Huntington’s, the researchers wrote.