Summary: A new study sheds light on demylination diseases like Multiple Sclerosis. Researchers discovered a blood clotting protein can leak into the central nervous system and prevent myelin production.
Source: Gladstone Institutes.
Picture a bare wire, without its regular plastic coating. It’s exposed to the elements and risks being degraded. And, without insulation, it may not conduct electricity as well as a coated wire. Now, imagine this wire is inside your brain.
That’s what happens in many diseases of the nervous system, such as multiple sclerosis (MS), spinal cord injuries, stroke, neonatal brain injuries, and even Alzheimer’s disease.
Much like that bare wire, the nerve fibers in the brain lose their protective coating, called myelin, and become extremely vulnerable. This leaves the nerve cells exposed to their environment and reduces their ability to transmit signals quickly, resulting in impaired cognition, sensation, and movement.
In disease, the brain seems to activate mechanisms to repair myelin, but cannot complete the process. For years, scientists have been trying to understand why these repair mechanisms are halted, as overcoming this obstacle holds great potential for treating disabling neurological diseases.
Katerina Akassoglou, PhD, and her research team at the Gladstone Institutes uncovered a promising new therapeutic strategy. Surprisingly, it’s associated with a protein in the blood.
They found that when fibrinogen (a blood-clotting protein) leaks into the central nervous system, it stops brain cells from producing myelin and, as a result, prevents repair.
The Culprit Is a Protein in the Blood
The cells needed to repair myelin already exist in the central nervous system. They are adult stem cells that travel to sites of damage, where they mature into myelin-producing cells. However, in many neurological diseases, this process is blocked. This is why the brain is unable to repair damaged myelin.
In an effort to understand why the brain can’t repair itself, scientists have focused on understanding what happens inside the cell. Akassoglou took a different approach.
“We thought it might be important to look instead at the toxic environment outside the cell, where blood proteins accumulate” said Akassoglou, senior investigator at Gladstone, professor of neurology at UC San Francisco (UCSF), and senior author of a study published by the scientific journal Neuron. “We realized that targeting the blood protein fibrinogen could open up the possibility for new types of therapies to promote brain repair.”
Akassoglou has spent much of her career studying the role of the blood-brain barrier and fibrinogen in neurological diseases. She previously showed that when blood leaks into the brain, fibrinogen causes inflammation by acting in brain immune cells, which can lead to brain damage.
In the new study, Akassoglou and her team uncovered another, yet unexpected effect of blood leaking into the brain.
“We found that fibrinogen stops adult stem cells from transforming into the mature cells that produce myelin,” explained first author of the study Mark Petersen, MD, a visiting scientist in Akassoglou’s laboratory and an assistant adjunct professor of pediatrics at UCSF. “This blockade could be harmful for regeneration in the brain.”
New Target Could Help Treat Multiple Sclerosis and Other Diseases
The regeneration of myelin in the brain is critical for diseases like MS, stroke, neonatal brain injury, and Alzheimer’s disease. Now, the scientific community might get closer to making that happen.
“Repairing myelin by eliminating the toxic effects of vascular damage in the brain is a new frontier in disease therapeutics,” said Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease and professor of neurology at UCSF. “This study could change the way we think about how to repair the brain.”
Researchers can now look for new ways to target fibrinogen as a way to restore regenerative functions in the central nervous system. This could lead to novel therapies to help patients with MS and many other diseases associated with myelin.
Gladstone’s Jae Kyu Ryu and UCSF’s Kae-Jiun Chang were equal second authors of the study. Other contributors include Sophia Bardehle, Andrew S. Mendiola, Wanjiru Kamau-Devers, Bernat Baeza-Raja, Catriona A. Syme, Michael D. Wu, Pamela E. Rios Coronado, and Anke Meyer-Franke from Gladstone; Ainhoa Etxeberria, Stephen P. J. Fancy, David H. Rowitch, Jonah R. Chan, and Eric J. Huang from UCSF; Andrea Thor, Eric A. Bushong, and Mark H. Ellisman from UC San Diego; Stephanie Yahn and Jae K. Lee from the University of Miami; Lauriane Pous and Christian Schachtrup from the University of Freiburg; Hans Lassmann from the Medical University of Vienna; May H. Han from Stanford University; and Martina Absinta and Daniel S. Reich from the National Institutes of Health (NIH).
Funding: The research conducted at Gladstone was funded by the National Institute of Neurological Diseases and Stroke Research Program Award (R35 NS097976), the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12-HD072222, K12-HD000850), the National Multiple Sclerosis Society (RG4985), and the United States Department of Defense (MS160082).
Source: Julie Langelier – Gladstone Institutes
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage” by Mark A. Petersen, Jae Kyu Ryu, Kae-Jiun Chang, Ainhoa Etxeberria, Sophia Bardehle, Andrew S. Mendiola, Wanjiru Kamau-Devers, Stephen P.J. Fancy, Andrea Thor, Eric A. Bushong, Bernat Baeza-Raja, Catriona A. Syme, Michael D. Wu, Pamela E. Rios Coronado, Anke Meyer-Franke, Stephanie Yahn, Lauriane Pous, Jae K. Lee, Christian Schachtrup, Hans Lassmann, Eric J. Huang, May H. Han, Martina Absinta, Daniel S. Reich, Mark H. Ellisman, David H. Rowitch, Jonah R. Chan, and Katerina Akassoglou in Neuron. Published online November 2 2017 doi:10.1016/j.neuron.2017.10.008
Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage
•Fibrinogen is a blood-derived inhibitor of oligodendrocyte differentiation
•Fibrinogen induces the BMP receptor pathway in OPCs
•The ACVR1 inhibitor DMH1 blocks fibrinogen’s inhibitory effects on OPCs
•Depletion of fibrinogen promotes remyelination in the CNS
Blood-brain barrier (BBB) disruption alters the composition of the brain microenvironment by allowing blood proteins into the CNS. However, whether blood-derived molecules serve as extrinsic inhibitors of remyelination is unknown. Here we show that the coagulation factor fibrinogen activates the bone morphogenetic protein (BMP) signaling pathway in oligodendrocyte progenitor cells (OPCs) and suppresses remyelination. Fibrinogen induces phosphorylation of Smad 1/5/8 and inhibits OPC differentiation into myelinating oligodendrocytes (OLs) while promoting an astrocytic fate in vitro. Fibrinogen effects are rescued by BMP type I receptor inhibition using dorsomorphin homolog 1 (DMH1) or CRISPR/Cas9 activin A receptor type I (ACVR1) knockout in OPCs. Fibrinogen and the BMP target Id2 are increased in demyelinated multiple sclerosis (MS) lesions. Therapeutic depletion of fibrinogen decreases BMP signaling and enhances remyelination in vivo. Targeting fibrinogen may be an upstream therapeutic strategy to promote the regenerative potential of CNS progenitors in diseases with remyelination failure.
“Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage” by Mark A. Petersen, Jae Kyu Ryu, Kae-Jiun Chang, Ainhoa Etxeberria, Sophia Bardehle, Andrew S. Mendiola, Wanjiru Kamau-Devers, Stephen P.J. Fancy, Andrea Thor, Eric A. Bushong, Bernat Baeza-Raja, Catriona A. Syme, Michael D. Wu, Pamela E. Rios Coronado, Anke Meyer-Franke, Stephanie Yahn, Lauriane Pous, Jae K. Lee, Christian Schachtrup, Hans Lassmann, Eric J. Huang, May H. Han, Martina Absinta, Daniel S. Reich, Mark H. Ellisman, David H. Rowitch, Jonah R. Chan, and Katerina Akassoglou in Neuron. Published online November 2 2017 doi:10.1016/j.neuron.2017.10.008