Central nervous system regeneration does not occur

Release date: 02-Dec-2012

Organisation: Postdoctoral Research Fellow at the South Australian Spinal Cord Injury Research Centre Dr Jillian Clark takes a look at a review by Dr LS Illis in the journal Spinal Cord (2012) 50: 259-263

Why does spontaneous nerve fibre regeneration not occur in the mature CNS? It is well known that some human tissues, such as blood and bone, retain their regenerative capacity throughout life. This principle does not hold for the mature human CNS and the explanation for this restricted regenerative capacity has been the subject of intensive investigation over the past century. There is consensus that that CNS failure to self-renew, or regenerate, is explained by: i) An inhibitory extracellular environment; and ii) The restricted regenerative capacity of its excitable cells (spinal neurons). We have previously reviewed research advances directed towards manipulating the inhibitory extracellular CNS environment (“Blocking the blockers”- SCIN 2011). Dr Illis (Spinal Cord 2012) critically reviews a body of literature that explores the restricted regenerative capacity of the CNS; focussing on evidence of a link to an evolutionarily conserved gene encoding for a protein kinase that regulates cell growth and size, known as mammalian target of Rapamycin (mTOR). Park and co-workers (2008) from Harvard University initially reported a link between mTOR, the down regulation of protein synthesis in damaged CNS neurons, and regenerative failure in mice1.   These Harvard University researchers found that mice deficient in a mTOR suppressor gene (phosphatase and tensin homolog deleted on chromosome 10 [PTEN]) had better neuron survival and demonstrated better nerve regeneration than wild type mice after optic nerve crush injury1. They went on to show better regeneration of spinal nerve pathways in PTEN deficient mice, this time specifically after spinal cord injury 2.   The authors studied two spinal cord injury models; the first being a T8 dorsal hemisection (less than half of the cord is damaged), and the second being a complete crush injury and examined evidence for nerve regeneration after 8, and 12 weeks. They found, similar to the damaged optic nerve1, that damaged spinal nerves were capable of regeneration, but this was seen only in the absence of PTEN2. This work provides exciting evidence that mTOR activation is sufficient to promote the: i) Compensatory sprouting of intact spinal nerve fibres; and ii) Regeneration of injured spinal nerve fibres.  However, it is as yet unclear if the regenerating nerve fibres observed in the damaged spinal cord of PTEN mutant mice formed new connections with their original targets2. Other recent evidence gives a hint that PTEN can be regulated by exercise, the hormone oestrogen and proinflammation.  Whilst Dr Illis’s review paper was in press, Drexel University researchers 3 studied the effects of cycling exercise on spinal neuron PTEN/mTOR expression in spinal cord injured rats. This work links exercise, a therapy that is used widely in rehabilitation, to growth control pathways that are capable of initiating a spinal nerve regenerative programme. Of importance for proof of principle the Drexel University researchers showed that the drug Rapamycin can block this exercise-induced effect on spinal mTOR expression. The hope is that new and exciting discoveries about the inhibitory activities of genes that regulate CNS regenerative programmes and possibly, promote activity-dependent plasticity in the intact spinal cord, will hold true for humans.  Chemical PTEN inhibitors are available, but it is too early to tell if these will be useful drugs for the treatment of early, or established spinal cord injury.  

What are the alternatives to pharmacological strategies for CNS regeneration? Dr LS Illis directs the spotlight towards exercise and electrical stimulation, citing evidence for “improved locomotion in persons with severe spinal cord injuries with body weight support”, and the ability of epidural spinal stimulation to elicit “step-like activity”. On a cautionary note, there is only limited evidence for functional improvements in locomotor activity in people with severe spinal cord injuries in response to treadmill training and more evidence will be needed before we could say that exercise stimulates spinal mTOR activation.  Intriguingly, mTOR/PTEN are best known for their roles in tumour biology, whilst PTEN has been linked to non-neoplastic disorders, such as familial Type 11 diabetes, Parkinson's disease, Autism.  The experimental work cited above 1,2,3, together with evidence for pharmacological PTEN inhibition in peripheral nerve injury4, gives a hint that the evolutionarily conserved PTEN/mTOR controlled signalling pathway plays a role in spinal cord injury regenerative failure via a mechanism that involves the down regulation of spinal neuron protein synthesis.  Only time will tell if the PTEN/mTOR pathway can be manipulated, either pharmacologically, or non-pharmacologically, to enhance the regenerative capacity of the injured human spinal cord.  

References  

1. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu B, Connolly L, Kramvis I, Sahin M, He Z. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008 Nov 7;322(5903):963-6.

2. Liu K, Lu Y, Lee JK, Samara R, Willenberg R, Sears-Kraxberger I, Tedeschi A, Park KK, Jin D, Cai B, Xu B, Connolly L, Steward O, Zheng B, He Z. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 2010 Sep;13(9):1075-81. Epub 2010 Aug 8.

3. Liu G, Detloff MR, Miller KN, Santi L, Houlé JD. Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Exp Neurol. 2012 Jan;233(1):447-56. Epub 2011 Nov 19.

4. Christie KJ, Webber CA, Martinez JA, Singh B, Zochodne DW. PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. Neurosci. 2010 Jul 7;30(27):9306-15.



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