Summary: Researchers have been able to restore limb mobility and partially reinsulate neurons in mouse models of MS with microRNA treatments.
Source: Cincinnati Children’s Hospital Medical Center.
Study sheds light on possible therapeutic approach for neurodegenerative disease.
Scientists partially re-insulated ravaged nerves in mouse models of multiple sclerosis (MS) and restored limb mobility by treating the animals with a small non-coding RNA called a microRNA.
In a study published online March 27 in Developmental Cell, researchers at Cincinnati Children’s Hospital Medical Center report that treatment with a microRNA called miR-219 restarted production of a substance called myelin in nerves of the central nervous system. Myelin forms a protective sheath around nerves, allowing them to efficiently transmit electrical impulses that stimulate movement.
Study authors administered miR-219 into the spinal columns and cerebrospinal fluid of mice with nerve coatings damaged by a chemical called lysolecithin or by autoimmune encephalomyelitis induced in the animals, which is used to model MS. Treatment with miR-219 reinvigorated the function of damaged cells called oligodendrocytes that produce myelin, which allowed the substance to reform and reinsulate nerves.
“We show that miR-219 targets multiple processes that inhibit myelin formation after nerve injury by the disease process, and that treatment with this microRNA partially restores myelination and limb function,” said Q. Richard Lu, PhD, lead investigator and scientific director of the Brain Tumor Center at Cincinnati Children’s. “It is conceivable that augmenting miR-219 treatment with other blockers of myelin regrowth may provide a multipoint treatment strategy for people with demyelinating diseases like MS.”
The authors stress that because their study was conducted in laboratory mouse models of disease, their data cannot at this stage be applied to clinical treatment in humans.
Lu’s laboratory studies how certain glial cell subtypes of the central and peripheral nervous system form, participate in regeneration and how they can transform into cancerous cells.
Molecular Silencer
MicroRNAs are short segments of RNA encoded on the chromosomes of cells. They regulate gene expression in cells by acting as molecular silencers, essentially blocking gene expression in certain situations.
A number of earlier research papers have pointed to the absence of miR-219 in the damaged nerves and tissues with certain neurodegenerative diseases like multiple sclerosis.
Lu and his colleagues tested the presence and effects of miR-219 in genetically-engineered mouse models of MS with chemically induced nerve coating damage by lysolecithin and autoimmune encephalomyelitis. They also deleted miR-219 in mice to test the impact this had on myelin-forming oligodendrocyte cells.
The absence of miR-219 allowed a surge of activity by several inhibitors of nerve re-myelination – including a protein called Lingo1. Further testing revealed that miR-219 is an essential part of a network that targets and blocks molecules that inhibit the ability of oligodendrocytes to form myelin.
This prompted the researchers to test treatment with miR-219 in their animal models. For this they used a miR-219 mimic – essentially a synthesized version of the microRNA. After administering the mimic to their mouse models, the researchers noted improved limb function and regeneration of the myelin coating on nerves.
Next steps
Lu and his colleagues are now trying to develop additional mimics of miR-219 and therapeutically effective formulations of the microRNA to ease its delivery – particularly into brain tissue. The researchers also continue to test the potential effectiveness of miR-219 treatment in different models of neurodegenerative disease.
Funding: Funding for the research came in part from grants from the National Institutes of Health (R01NS072427, R01NS075243, R01NS065808, R21NS087474) and the National Multiple Sclerosis Society (NMSS-4727, RG 4172-A-4).
Source: Nick Miller – Cincinnati Children’s Hospital Medical Center
Image Source: NeuroscienceNews.com image is credited to Cincinnati Children’s.
Original Research: Abstract for “miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS” by Haibo Wang, Ana Lis Moyano, Zhangyan Ma, Yaqi Deng, Yifeng Lin, Chuntao Zhao, Liguo Zhang, Minqing Jiang, Xuelian He, Zhixing Ma, Fanghui Lu, Mei Xin, Wenhao Zhou, Sung Ok Yoon, Ernesto R. Bongarzone, and Q. Richard Lu in Developmental Cell. Published online March 27 2017 doi:10.1016/j.devcel.2017.03.001
[cbtabs][cbtab title=”MLA”]Cincinnati Children’s Hospital Medical Center “MicroRNA Treatment Restores Myelin and Limb Function in Multiple Sclerosis: Mouse Study.” NeuroscienceNews. NeuroscienceNews, 27 March 2017.
<https://neurosciencenews.com/microrna-myelin-ms-6297/>.[/cbtab][cbtab title=”APA”]Cincinnati Children’s Hospital Medical Center (2017, March 27). MicroRNA Treatment Restores Myelin and Limb Function in Multiple Sclerosis: Mouse Study. NeuroscienceNew. Retrieved March 27, 2017 from https://neurosciencenews.com/microrna-myelin-ms-6297/[/cbtab][cbtab title=”Chicago”]Cincinnati Children’s Hospital Medical Center “MicroRNA Treatment Restores Myelin and Limb Function in Multiple Sclerosis: Mouse Study.” https://neurosciencenews.com/microrna-myelin-ms-6297/ (accessed March 27, 2017).[/cbtab][/cbtabs]
Abstract
miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS
Highlights
•miR-219 is critical for oligodendrocyte differentiation and myelination in murine CNS
•miR-338 deletion exacerbates the dysmyelination phenotype in miR-219-deficient mice
•miR-219 targets stage-specific inhibitors and Lingo1-Etv5 to promote CNS myelination
•miR-219 mimics augment remyelination and functional recovery in demyelinating models
Summary
A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.
“miR-219 Cooperates with miR-338 in Myelination and Promotes Myelin Repair in the CNS” by Haibo Wang, Ana Lis Moyano, Zhangyan Ma, Yaqi Deng, Yifeng Lin, Chuntao Zhao, Liguo Zhang, Minqing Jiang, Xuelian He, Zhixing Ma, Fanghui Lu, Mei Xin, Wenhao Zhou, Sung Ok Yoon, Ernesto R. Bongarzone, and Q. Richard Lu in Developmental Cell. Published online March 27 2017 doi:10.1016/j.devcel.2017.03.001
