Unlike in many other animals, injured nerve fibres in the mammalian central nervous system do not regenerate – at least not spontaneously. A lot of research has gone in to finding ways to coax them to do so, unfortunately with only modest success. The main problem is that there are many reasons why central nerve fibres don’t regenerate after an injury – tackling them singly is not sufficient. A new study takes a combined approach to hit two distinct molecular pathways in injured nerves and achieves substantial regrowth in an animal model.
Many lower vertebrates, like frogs and salamanders, for example, can regrow damaged nerves quite readily. And even in mammals, nerves in the periphery will regenerate and reconnect, given enough time. But nerve fibres in the brain and spinal cord do not regenerate after an injury. Researchers trying to solve this problem focused initially on figuring out what is different about the environment in the central versus the peripheral nervous system in mammals.
It was discovered early on that the myelin – the fatty sheath of insulation surrounding nerve fibres – in the central nervous system is different from that in the periphery. In particular, it inhibits nerve growth. A number of groups have tried to figure out what components of central myelin are responsible for this activity. Myelin is composed of a large number of proteins, as well as lipid membranes. One of these, subsequently named Nogo, was discovered to block nerve growth. This discovery prompted understandable excitement, especially because an antibody that binds that protein was found to promote regrowth of injured spinal nerves in the rat. (It even prompted a film, Extreme Measures, with Gene Hackman and Hugh Grant – an under-rated thriller with some surprisingly accurate science and some very serious medical malfeasance).
Unfortunately, the regrowth in rats that is promoted by blocking the Nogo protein is very limited. Similarly, mice that are mutant for this protein or its receptor show very minor regeneration. What is observed in some cases is extra sprouting of uninjured axons downstream of the spinal injury site. This can lead to some minor recovery of function but it’s really remodelling, rather than regeneration.
But it does suggest an answer to the question: why would we have evolved a system that seems actively harmful, that prevents regeneration after an injury? Well, first, the selective pressure in mammals to be able to regenerate damaged nerves is probably not very great, simply because injured animals would not typically get the chance to regenerate in the wild. And second, it suggests that the function of proteins like Nogo may not be to prevent regeneration but to prevent sprouting of nerve fibres after they have already made their appropriate connections. A lot of effort goes in to wiring the nervous system, with exquisite specificity – once that wiring pattern is established, it probably pays to actively keep it that way.
There are a number of reasons why blocking the Nogo protein does not allow nerves to fully regenerate. First, it is not the only protein in myelin that blocks growth – there are many others. Second, the injury itself can give rise to scarring and inflammation that generates a secondary barrier. And third, neurons in the mature nervous system may simply not be inclined to grow. (Not only that – the distances they may have to travel in the fully grown adult may be orders of magnitude longer than those required to wire the nervous system up during development. There are nerves in an adult human that are almost a metre long but these connections were first formed in the embryo when the distance was measured in millimetres.)
This last problem has been addressed more recently, by researchers asking if there is something in the neurons themselves that changes over time – after all, neurons in the developing nervous system grow like crazy. That propensity for growth seems to be dampened down in the adult nervous system – again, once the nervous system is wired up, it is important to restrict further growth.
Researchers have therefore looked for biochemical differences between young (developing) neurons and mature neurons that have already formed connections. The hope is that if we understand the molecular pathways that differ we might be able to target them to “rejuvenate” damaged neurons, restoring their internal urge to grow. The lab of Zhigang He at Harvard Medical School has been one of the leaders in this area and has previously found that targeting either of two biochemical pathways allowed some modest regeneration of injured neurons. (They study the optic nerve as a more accessible model of central nerve regrowth than the spinal cord).
In a new study recently published in Nature, they show that simultaneously blocking both these proteins leads to remarkably impressive regrowth – far greater than simply an additive effect of blocking the two proteins alone. The two proteins are called PTEN and SOCS3 – they are both intracellular regulators of cell growth, including the ability to respond to extracellular growth factors. The authors used a genetic approach to delete these genes two weeks prior to an injury and found that regrowth was hugely promoted. That is obviously not a very medically useful approach however – more important is to show that deleting them after the injury can permit regeneration and indeed, this is what they found. Presumably, neurons in this “grow, grow, grow!” state are either insensitive to the inhibitory factors in myelin or the instructions for growth can override these factors.
They went on to characterise the changes that occur in the neurons when these genes are deleted and observed that many other proteins associated with active growth states are upregulated, including ones that get repressed in response to the injury itself. The hope now is that drugs may be developed to target the PTEN and SOCS3 pathways in human patients, especially those with devastating spinal cord injuries, to encourage damaged nerves to regrow. As with all such discoveries, translation to the clinic will be a difficult and lengthy process, likely to take years and there is no guarantee of success. But compared to previous benchmarks of regeneration in animal models, this study shows what looks like real progress.
Sun F, Park KK, Belin S, Wang D, Lu T, Chen G, Zhang K, Yeung C, Feng G, Yankner BA, & He Z (2011). Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature, 480 (7377), 372-5 PMID: 22056987