Schwann cells protect nerves against blood clotting factors that cause degeneration — ScienceDaily
Salk researchers first discovered that coagulation proteins may unexpectedly degrade nerves – and how nerve-backed glial cells (including Schwann cells) provide protection. The finding was published in the journal PLOS Genetics on March 14, 2019, indicating that Schwann cells protect nerves by blocking this blood coagulation protein and other potentially destructive enzymes released by muscle cells. This work may affect a variety of diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer's disease or schizophrenia.
"This is the first study to show that molecules normally associated with blood clotting, thrombin, have biological functions outside the liver system and play an important role in neurodegeneration," Professor Salk Kuo-Fen Lee, Senior author of the paper. "We further demonstrate that Schwann cells protect the nerves from thrombin. The results are surprising and raise interesting questions about how to form and maintain synapses in health and disease."
Schwann cells form protective insulation around the linear protrusions of the nerves called axons and help form synapses, the contacts that chemical signals pass between cells. To better understand the role of Schwann cells in neurological health, the Salk team studied a specific synapse called the neuromuscular junction (NMJ) that interacts with Schwann cells, nerves and muscles.
In the absence of Schwann cells, NMJ synapses in the mouse model degenerated two days later, confirming their role in synaptic growth. The researchers found that without Schwann cells, the signaling molecule in acetylcholine – NMJ – is the culprit in causing neurodegeneration. When the researchers conducted more in-depth research to find out the cause, they discovered a previously unknown mechanism: acetylcholine causes muscle cells to release coagulation proteins, called thrombin, and other enzymes that degrade nerves. In healthy nerves, Schwann cells release molecules that block thrombin to protect their synapses.
"We are amazed that Schwann cells indirectly maintain neuromuscular synapses by inhibiting the negative factors of active muscle release. One of the factors is thrombin, most notably its role in the formation of thrombosis," former Salk researcher Thomas Gould said the author of the paper is now an assistant professor at the University of Nevada's Reno School of Medicine.
To confirm the effect of thrombin on NMJ, the researchers studied a mouse model of the absence or absence of thrombin and found that these mice had less axonal degeneration. These results confirm that thrombin plays a role in axonal degeneration.
"This study provides an understanding of the genetic and molecular pathways that alter triggering and maintenance," said Helen McLoraine, chairman of molecular neurobiology, Lee. “The next step is to understand how thrombin and other enzymes disrupt synaptic mechanisms – and the ultimate goal is to create a disease intervention – such as ALS, MS and Alzheimer's – which involves thrombin accumulation or regulation abnormalities.”
Other authors include: Bertha Dominguez and Fred de Winter of Salk; Gene W. Yeo, Patrick Liu, Balaji Sundararaman, Thomas Stark and Anthony Vu of the University of California, San Diego; Jay L. Degen of the Cincinnati Children's Hospital Research Foundation; And Weichun Lin of the University of Texas Southwestern Medical Center.
Funding for this work comes from the National Institutes of Health (GM103554, NS107922, NS055028, NS075449, HG004659, HL096126, NS044420, NS060833, AG0476669, OD023076, MH114831, AG062232), the Clayton Foundation, the Schlink Foundation, Gemcon Family Foundation, Brown Foundation and Freeburg Foundation.
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