Scientists ID mechanisms that could drive neurodegeneration in MS

Failure to repair lost myelin linked directly to nerve cell death: Study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A close-up illustration of damaged myelin.

Activation of a protein called DLK may drive the death of nerve cells that have been demyelinated, or lost their protective myelin coating, in multiple sclerosis (MS), according to a new study from U.S. researchers.

The findings shed light on how a failure to repair lost or damaged myelin is directly linked to neurodegeneration, and point to DLK as a potential new target for treatment approaches in MS.

Indeed, the researchers suggest that “effective remyelination” ā€” the regenerative process by which new myelin sheaths are produced ā€” may improve nerve cell survival.

ā€œWe demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as [a] protective strategy for chronically demyelinated neurons,ā€ the team wrote.

The study, ā€œRemyelination protects neurons from DLK-mediated neurodegeneration,ā€ was published in the journal Nature Communications.

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In MS, the immune system mistakenly launches damaging inflammatory attacks against myelin, leading to progressive demyelination.Ā While the body has natural mechanisms to promote remyelination, or myelin repair, this process is impaired in MS and canā€™t completely compensate for ongoing demyelination.

Itā€™s believed that chronic demyelination leaves nerve cells without important metabolic support, ultimately making them vulnerable to degenerating and dying off ā€” the neurodegeneration that’s a hallmark of MS.

Yet, studies investigating how exactly impaired remyelination leads to neurodegeneration in MS are lacking. Thatā€™s in part because existing mouse models tend to have very fast remyelination ā€” much faster than what actually occurs in humans.

Now, to overcome that limitation, a team of scientists, led by researchers at Oregon Health & Science University (OHSU), developed and compared two new mouse models genetically engineered to experience significant demyelination of nerve cells.

One of these mouse models was capable of remyelination, while the other was further engineered to have impaired remyelination, driving a chronic demyelinated state similar to whatā€™s seen in MS lesions.

Both mouse models developed motor symptoms consistent with demyelination, but the mice capable of remyelination eventually recovered while those with impaired remyelination continued to decline.

Early on, both mouse models had an increase in blood levels of neurofilament light chain (NfL), a biomarker of nerve damage. However, in mice in whom remyelination occurred, NfL eventually returned to levels observed in healthy mice.

This was not the case in mice with chronic demyelination, where signs of ongoing nerve cell damage and increased cell death were observed. These mice also showed signs of altered inflammatory processes and impaired maturation of myelin-producing cells.

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An oversized human hand holds a mouse next to a trio of test tubes in this laboratory illustration.

Genetic modifications to myelin-making cells boost myelin repair

Researcher credited with developing ‘useful’ new mouse model

The scientists identified a signaling pathway that appears to drive cell death in the chronically demyelinated cells of this mouse model. It involved the activation of DLK, or dual leucine zipper kinase, which subsequently activated pathways related to cellular stress and injury.

Inhibiting DLK with a drug or genetic techniques was able to prevent cell death in the mice with impaired remyelination.

[These findings] suggest that inhibiting this pathway could be beneficial in preventing neurodegeneration or slowing the progression of MS.

According to Gregory Duncan, PhD, a postdoctoral researcher at OHSU and the study’s first author, was credited in a university news story with developing this mouse model and discovering the link between the protein pathway and neuron death.

These findings ā€œsuggest that inhibiting this pathway could be beneficial in preventing neurodegeneration or slowing the progression of MS,ā€Ā  Duncan said.

However, the scientist noted that because DLK also plays other important roles in the body, researchers will ā€œhave to be cautious,ā€ when designing treatments that target it.

ā€œAny therapeutics developed would need to be targeted to avoid side effects and still be useful,ā€ Duncan said.

The research team noted that these new mouse models may prove helpful to other scientists seeking to learn more about MS disease mechanisms.

ā€œThese genetic models ā€¦ are going to be useful for not only our lab, but probably many others to test neuroprotective strategies in this ongoing work on MS and other demyelinating diseases,ā€ said Ben Emery, PhD, an associate professor in the OHSU School of Medicine and the study’s corresponding author.

 


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