Spinal cord regeneration: Without p75NTR you've got some nerve - Cell Signaling Update

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Spinal cord regeneration: Without p75^NTR you've got some nerve

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p75NTR displaces the active form of RhoA from its complex with Rho-GDI thus causing the inhibition of central nervous system (CNS) nerve growth. These results may offer a practical therapeutic approach for treating injuries of the central nervous system.

Unlike those of the peripheral nervous system, the neurons of the central nervous system (CNS) are unable to regenerate once damaged. Previous research has shown that this CNS specific growth inhibition is due to the myelin-derived inhibitory proteins myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (OMgp) and Nogo-A. These proteins work in conjunction with the Nogo receptor (NgR), which binds directly to the extracellular region of the p75 neurotrophin receptor (p75^NTR). p75^NTR in turn modulates the activity of the NGF-receptor to regulate neuronal apoptosis. The small GTPase Rho has been implicated in mediating myelin associated growth inhibition. In its active GTP-bound form, RhoA stiffens the actin cytoskeleton. This causes the collapse of growth cones and further inhibits neuronal elongation. Yeast two-hybrid studies have shown that the inactive GDP-bound RhoA interacts with p75^NTR while active GTP-bound RhoA does not.

Work by Yamashita et al. has now elaborated the signaling mechanism mediating CNS neuron growth inhibition. Rho proteins in the GDP-bound form interact with Rho-GDI, thus preventing RhoA from being converted to the active GTP-bound form that translocates to the membrane. Yamashita et al. show that p75^NTR interacts with RhoA in complex with Rho-GDI, with MAG and Nogo strengthening this interaction. Recombinant p75^NTR did not bind RhoA directly; in contrast, it does bind Rho-GDI both alone and in complex with RhoA. The p75^NTR binding domain is located in the fifth alpha helix of the intracellular domain (ICD), a sequence very similar to that of a known RhoA-activating peptide.

The authors examined the effect of the interaction between Rho-GDI and the helical domain (HD) of p75^NTR on its ability to inhibit the GDP/GTP exchange reaction of RhoA. They found that p75^NTR releases RhoA from Rho-GDI in vitro, consistent with the idea that p75^NTR acts as a Rho-GDI displacement factor. Pep5, a ligand to the p75^NTR HD, inhibits p75^NTR binding to Rho-GDI when fused to the HIV TAT N-terminal domain to facilitate membrane transfer. TAT-Pep5 also abolishes the responses to both MAG and Nogo in cultured neurons.

Although it is unknown whether p75^NTR also suppresses axonal growth via Rho-independent mechanisms, these results may offer a practical therapeutic approach for treating injuries of the CNS by allowing spinal cord regeneration.

Brenda Riley, Assistant Editor
Signaling Gateway

References

Yamashita, Toshi Tohyama, Masaya The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nature Neuroscience, 6, 461–467 (2003) 10.1038/nn1045
Kaplan, David R. Miller, Freda D. Axon growth inhibition: signals from the p75 neurotrophin receptor. Nature Neuroscience, 6, 435–436 (2003) 10.1038/nn0503-435