Gene Manipulations Enable Regeneration of Injured Spinal Tissue

Inactivation of the PTEN gene in corticospinal tract (CST) axons enabled these cells to regenerate and reestablish functional nerve connections in a rodent spinal injury model.

PTEN (phosphatase and tensin homologue) acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly. Mutations of this gene contribute to the development of certain cancers. When the PTEN enzyme is functioning properly, it acts as part of a chemical pathway that signals cells to stop dividing and causes cells to undergo programmed cell death (apoptosis) when necessary. These functions prevent uncontrolled cell growth that can lead to the formation of tumors. There is also evidence that the protein made by the PTEN gene may play a role in both cell movement and adhesion of cells to surrounding tissues. One of the pathways under direct PTEN control is called mTOR, which is a key regulator of cell growth and is dysregulated in many human diseases, especially certain cancers.

A team of collaborators from the University of California, Irvine (USA), the University of California, San Diego, and Harvard University (Cambridge, MA, USA) developed a method for increasing mTOR activity in axons through the conditional deletion of PTEN. They reported in the August 8, 2010, online edition of the journal Nature Neuroscience that increased mTOR activity in damaged nerve tissue enhanced compensatory sprouting of uninjured CST axons and enabled successful regeneration of a cohort of injured CST axons past a spinal cord lesion. These regenerating CST axons possessed the ability to reform synapses in spinal segments distal to the injury.

"Until now, such robust nerve regeneration has been impossible in the spinal cord,” said contributing author Dr. Oswald Steward, professor of anatomy and neurobiology at the University of California, Irvine. "Paralysis and loss of function from spinal cord injury has been considered untreatable, but our discovery points the way toward a potential therapy to induce regeneration of nerve connections following spinal cord injury in people. The devastating consequences of spinal cord injury occur even though the spinal cord below the level of injury is intact. All these lost functions could be restored if we could find a way to regenerate the connections that were damaged.”

Based on these findings, the investigators believe that modulating neuronal intrinsic PTEN/mTOR activity represents a potential therapeutic strategy for promoting axon regeneration and functional repair after adult spinal cord injury. To this end, they are now studying whether the PTEN-deletion treatment leads to actual restoration of motor function in mice with spinal cord injury.

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University of California, Irvine
University of California, San Diego
Harvard University