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Stretched to the Breaking Point

:  Like beads on a string, periodic swellings can appear on nerve fibers called “axons” after traumatic injury.  At each swelling site, there is mechanical breakage of individual microtubules that act as “railroad tracks” within the axons, causing accumulation of their transported cargoes.   Breakage of different microtubules at different locations along the axons results the periodic arrangement of the swellings.  This represents a newfound process of “partial interruption of axonal transport” found after axon stretch injury in culture (top two panels) and in humans with traumatic brain injury (bottom panel).

With this year’s Super Bowl setting a record for being the most-viewed show in U.S. television history, concussions – more technically, mild traumatic brain injury (TBI) – have probably been on many a mind this week. TBI has long been a leading cause of death and disability, with over 1.7 million cases in the US alone each year.
 
Misshapened, swollen nerve fibers called axons in the post-mortem brain tissue of TBI patients have been noted by pathologists for years. They assumed the swellings arose from a complete interruption in what the axons were normally transporting between nerve cells. Due to their elastic nature, white-matter axons are susceptible to damage by the stretch and strain produced during TBI.
 
Using a high-powered microscope called TEM, for transmission electron microscopy, a team from Penn Medicine viewed damaged axons in two ways to gain a better idea of what causes the damage: in those grown in the lab and stretched mechanically and in those from post-mortem samples from TBI patients. In both types of axons, they found at each site of swelling mechanical breakage of individual microtubules – tubes for transporting proteins within a cell. This break in the cell’s transport system causes accumulation of the protein cargo. Breakage of different microtubules at different locations on the axons can also cause a series of swellings along the entire length, creating the appearance of beads on a string.

 Douglas Smith, MD, director of Penn's Center for Brain Injury and Repair, describes this breakage as “partial interruption of axonal transport,” in the current issue of Experimental Neurology.
 
They found that typically less than a third of microtubules were broken in any region of the mechanically stretched axons.  At the break points, axons appeared squiggly since the broken microtubules prevent the axons from snapping back to their pre-injury straightness and length. Within hours, these sites of microtubule breaks in damaged axons evolved into swellings. This suggests transport of proteins along an axon may be halted along one broken microtubule, yet can proceed through the same region of the axon via other intact microtubules. Similar squiggly axons and swellings along axons have been observed shortly following TBI in humans, suggesting the same mechanism of primary microtubule failure occurs in people as well.
 
Smith always has great axon analogies: "Think of an axon as a bungee cord, with the elastic strands inside representing tracks of microtubules. If the bungee cord is stretched too rapidly, some of the strands break and you get a squiggly bungee cord. But, for axons, the breaks in microtubules also cause transported proteins to slowly accumulate, like a train’s cargo being dumped at a disconnection point of a railroad track. If the swelling gets too large at any region of the axon, the entire axon may begin to disintegrate."

These findings, he says, underscore the notion that TBI causes destabilization of microtubules and how a series of swellings can occur in axons. The Center’s team is now looking to see if microtubule-stabilizing drugs might be a good avenue for post-TBI treatment. 

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ResearchBlogging.org Tang-Schomer MD, Johnson VE, Baas PW, Stewart W, & Smith DH (2012). Partial interruption of axonal transport due to microtubule breakage accounts for the formation of periodic varicosities after traumatic axonal injury. Experimental neurology, 233 (1), 364-72 PMID: 22079153

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