Regenerating the central nervous system by making neurons young again

Andrew John Murray, Derryck Shewan

Research output: Contribution to conferencePoster

Abstract

The search for an effective therapy for repairing the damaged central nervous system (CNS) remains one of the greatest challenges facing medical science. Damage to the brain or spinal cord is so debilitating because the adult mammalian CNS does not regenerate after injury. However, the immature nervous system can regenerate, and thus the ability of neurons to regrow their axonal processes is only lost after birth. A number of reasons have been proposed for this developmental decline in regenerative capacity. In particular, the expression of several axon growth-inhibitory proteins in the CNS nerve environment has formed a major focus of biomedical research for many years. Despite diverse attempts to override the inhibitory effects of these proteins, a practicable therapy for CNS injury remains elusive.

Intriguingly, embryonic neurons are not only able to regenerate in the immature CNS, but can also grow extensive axons when transplanted into the adult CNS. In contrast, adult neurons do not regenerate when transplanted into the embryonic CNS. This strongly suggests that intrinsic changes occur within neurons as they develop that render them unable to regrow injured axons. Intracellular signalling molecules transduce signals received from the extracellular environment. Cyclic-adenosine monophosphate (cAMP) is a particularly important intracellular signalling molecule, known to be involved in neuronal responses to a number of axon growth-promoting and inhibitory guidance cues. Endogenous levels of cAMP have been shown to decline at the time the nervous system loses its regenerative capacity. Artificial elevation of cAMP activity can overcome growth-inhibitory signals and enhance axon outgrowth. Thus elevation of levels of cAMP activity appears to encourage older neurons to behave like their younger counterparts in regenerating axons, providing great encouragement for future therapeutic interventions.

However, given the diverse roles of cAMP in a number of important cell functions, we are concerned that manipulation of its activity could have detrimental consequences. Our current research therefore focuses on downstream molecules activated by cAMP, protein kinase A (PKA) and the exchange protein activated by cAMP (Epac). Before the recent identification of Epac, PKA was thought to mediate all cAMP signalling. It is now known, however, that Epac can mediate cAMP signalling independently of PKA. We report here the first detailed study of Epac in the nervous system. Like cAMP, Epac’s expression is developmentally regulated. Moreover, selective activation of Epac induces axon regeneration to a similar or greater extent as activation of cAMP itself, suggesting that Epac could be targeted to promote axon regeneration whilst potentially leaving cAMP and PKA to carry out other cellular functions unhindered. We also find that manipulation of other signalling molecules in combination with cAMP promotes extensive regeneration of adult neurons. These results provide real optimism that such strategies could lead to successful therapeutic interventions for repairing the damaged CNS.
Original languageEnglish
Publication statusPublished - 14 Feb 2007
EventSET for Britain, House of Commons, Westminster - London, United Kingdom
Duration: 14 Feb 2007 → …

Exhibition

ExhibitionSET for Britain, House of Commons, Westminster
CountryUnited Kingdom
CityLondon
Period14/02/07 → …

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Cyclic AMP
Central Nervous System
Neurons
Axons
Cyclic AMP-Dependent Protein Kinases
Proteins
Nervous System
Regeneration
Adenosine Kinase
Nervous System Trauma
Aptitude
Therapeutics
Growth
Cues
Biomedical Research
Spinal Cord
Cell Count
Parturition

Cite this

Murray, A. J., & Shewan, D. (2007). Regenerating the central nervous system by making neurons young again. Poster session presented at SET for Britain, House of Commons, Westminster, London, United Kingdom.

Regenerating the central nervous system by making neurons young again. / Murray, Andrew John; Shewan, Derryck.

2007. Poster session presented at SET for Britain, House of Commons, Westminster, London, United Kingdom.

Research output: Contribution to conferencePoster

Murray, AJ & Shewan, D 2007, 'Regenerating the central nervous system by making neurons young again' SET for Britain, House of Commons, Westminster, London, United Kingdom, 14/02/07, .
Murray AJ, Shewan D. Regenerating the central nervous system by making neurons young again. 2007. Poster session presented at SET for Britain, House of Commons, Westminster, London, United Kingdom.
Murray, Andrew John ; Shewan, Derryck. / Regenerating the central nervous system by making neurons young again. Poster session presented at SET for Britain, House of Commons, Westminster, London, United Kingdom.
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