Among the principal obstacles to regenerating spinal cord and brain cells after injury is the "braking" machinery in neurons that prevents regeneration. While peripheral nerves have no such machinery and can readily regenerate, central nervous system (CNS) neurons have their brakes firmly in place and locked.
Now, two groups of scientists have independently found a new component of that braking machinery, adding to understanding of the regulation of neuronal regeneration and of possible treatments to switch off the brakes on regrowth of spinal cord or brain tissue.
The two groups--one group led by Jong Bae Park, Glenn Yiu, and colleagues from Children's Hospital Boston and the other led by Sha Mi and colleagues of Biogen Idec, Inc.--discovered that a protein variously called TAJ or TROY acts as an important part of the receptor on neurons that responds to growth-inhibitory molecules in myelin. Specifically, these molecules prevent the growth of the cablelike axons of injured neurons. Myelin is the fatty sheath that encases neurons and acts as an insulator and aid to the transmission of nerve impulses.
Researchers knew that CNS neurons had receptors on their surface that accepted the inhibitory molecules--like a key fitting a lock--and switched-on inhibitory signaling within the neuron. They had also shown that a protein called p75 could function as a component of the complex of proteins that make up this receptor. The puzzle, however, was that p75 is not widely made in the adult neurons in which this inhibitory receptor complex is known to function.
The two research groups turned their attention to TAJ/TROY because it is a member of the same family of receptor proteins--called TNF receptors--as p75. Their experiments revealed that TAJ/TROY is produced throughout the adult brains of mice. Also, they found that TAJ/TROY readily fits into the inhibitory receptor complex and that the resulting receptor complex switches-on the inhibitory machinery within neurons. Also, they found that treating neurons with a nonfunctional version of TAJ/TROY abolished neurons' response to the "braking" molecules produced by myelin and encouraged neuron growth.
"Given the limited expression of p75, the discovery of TAJ function is an important step for understanding the regulation of axon regeneration," wrote Mi and colleagues.
Wrote Park and colleagues, "The implication that more than one TNF receptor member may be involved in myelin inhibition adds a new level of complexity to designing therapeutic strategies for treating CNS injury." They cited studies showing that TNF receptors are expressed in many types of cells in the CNS and are intimately involved in inflammatory responses that also play a role--perhaps harmful, perhaps beneficial to regeneration or recovery--in regulating response to injury. "Further characterization of the underlying mechanisms of these findings and their relation to myelin inhibition may provide important insights into designing therapeutic strategies to block myelin inhibition and cell death in the context of CNS injury," they wrote.
Jong Bae Park, Glenn Yiu, Shinjiro Kaneko, Jing Wang, Jufang Chang, and Zhigang He: "A TNF Receptor Family Member, TROY, Is a Coreceptor with Nogo Receptor in Mediating the Inhibitory Activity of Myelin Inhibitors"
Zhaohui Shao, Jeffrey L. Browning, Xinhua Lee, Martin L. Scott, Sveltlana Shulga-Morskaya, Norm Allaire, Greg Thill, Melissa Levesque, Dinah Sah, John M. McCoy, Beth Murray, Vincent Jung, R. Blake Pepinsky, and Sha Mi: "TAJ/TROY, an Orphan TNF Receptor Family Member, Binds Nogo-66 Receptor 1 and Regulates Axonal Regeneration"
Park et al.: The other members of the research team include Jong Bae Park, Glenn Yiu, Shinjiro Kaneko, Jing Wang, Jufang Chang, and Zhigang He of Children's Hospital and Harvard Medical School. This study was supported by grants from the John Merck Fund and NIH. Shao et al.: The other members of the research team include Zhaohui Shao, Jeffrey L. Browning, Xinhua Lee, Martin L. Scott, Sveltlana Shulga-Morskaya, Norm Allaire, Greg Thill, Melissa Levesque, Dinah Sah, John M. McCoy, Beth Murray, Vincent Jung, R. Blake Pepinsky, and Sha Mi of Biogen Idec, Inc.
Publishing in Neuron, Volume 45, Number 3, February 3, 2005, pages 345-351 (Park et al.) and 353-359 (Shao et al.) www.neuron.org