Researchers identify precision medicine to regenerate corticospinal tract axons.


Chronic spinal cord injury (SCI) is a formidable hurdle that prevents a large number of injured axons from crossing the lesion, particularly the corticospinal tract (CST). Patients inflicted with SCI would often suffer a loss of mobility, paralysis, and interferes with activities of daily life dramatically. While physical therapy and rehabilitation would help the patients to cope with the aftermath, axonal regrowth potential of injured neurons was thought to be intractable.  Now, researchers at the Hong Kong University of Science and Technology (HKUST) have found a way to stimulate the growth of axons, which may spell the dawn of a new beginning on chronic SCI treatments.  The study is published in The Journal of Neuroscience.

Previous studies show that the corticospinal tract is an aggregation of upper motor neuron nerve fibres (axons) that travel from the cerebral cortex and terminate either in the spinal cord and is involved in control of motor functions of the body.The corticospinal tract conducts impulses from the brain to the spinal cord. It is made up of a lateral and anterior tract. The corticospinal tract is involved in voluntary movement.  The majority of corticospinal tract axons cross over in the medulla, resulting in muscles being controlled by the opposite side of the brain.

The current study found that the deletion of the PTEN gene would enhance compensatory sprouting of uninjured CST axons. The data findings also showed that the deletion of the PTEN gene up-regulated the activity of another gene, the mammalian target of rapamycin (mTOR), which promoted regeneration of CST axons.

The team initiated PTEN deletion on mice after pyramidotomy. Similar treatment procedures were carried out on a 2nd group 4 months after severe spinal cord injuries, and a 3rd group after 12 months. The results showed a regenerative response of CST axons in all 3 samples, showing that PTEN deletion stimulates CST sprouting and regeneration, even though the injury was sustained a long time ago.

As one of the long descending tracts controlling voluntary movement, the corticospinal tract (CST) plays an important role for functional recovery after spinal cord injury, state the team.  The regeneration of CST has been a major challenge in the field, especially after chronic injuries. They go on to add that they have developed a strategy to modulate PTEN/mTOR signaling in adult corticospinal motor neurons in the post-injury paradigm.

The data findings show that it not only promoted the sprouting of uninjured CST axons, it also enabled the regeneration of injured axons past the lesion in a mouse model of spinal cord injury, even when treatment was delayed up to 1 year after the original injury. The results considerably extend the window of opportunity for regenerating CST axons severed in spinal cord injuries.

The team explain that compared with acute injury, axons face more barriers to regenerate after chronic SCI. Previously, scientists have shown that Axon retraction may further increase the distance that axons need to travel; extracellular matrices, which become well consolidated around the chronic lesion site, also increases inhibition. Earlier studies show that neuronal aging may also add obstacles to regrowth. In light of all of these challenges, it is indeed surprising to find that CST axons can still regenerate after 1 year.

The researchers surmise that it is interesting to find that chronically injured neurons retain the ability to reform tentative synaptic connections.  They go on to conclude that PTEN inhibition can be targeted on particular neurons, which means that they can apply the procedure specifically on the region of interest as they continue their research.

Source:  Hong Kong University of Science and Technology (HKUST)

Regeneration of Mouse Corticospinal Tract Axons.  This sagittal section shows the regeneration of mouse corticospinal tract axons (red) 7 months after Pten deletion was initiated in motor cortex. Pten deletion was initiated 1 year after spinal cord injury in this mouse. Green labels glial fibrillary acidic protein.  Credit:  Division of Life Science, HKUST.

Regeneration of Mouse Corticospinal Tract Axons. This sagittal section shows the regeneration of mouse corticospinal tract axons (red) 7 months after Pten deletion was initiated in motor cortex. Pten deletion was initiated 1 year after spinal cord injury in this mouse. Green labels glial fibrillary acidic protein. Credit: Division of Life Science, HKUST.

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