Blocking Nerve Growth Factor Receptor Enables Human Nervous System Regeneration

The mystery of why the human nervous system is unable to regenerate may have been at least partially solved with the identification of a protein called p75 that seems to block the repair of damaged nerve cells.

Investigators at the Salk Institute for Biological Studies (La Jolla, CA, USA) explained that the p75 neurotrophin receptor, a member of the tumor necrosis factor receptor superfamily, was required as a co-receptor for the Nogo receptor (NgR - reticulon 4 receptor) to mediate the activity of regeneration inhibitors such as Nogo. The Nogo receptor mediates axonal growth inhibition and may play a role in regulating axonal regeneration and plasticity in the adult central nervous system.

p75, also called nerve growth factor receptor, contains an extracellular domain containing four 40-amino acid repeats with six cysteine residues at conserved positions followed by a serine/threonine-rich region, a single transmembrane domain, and a 155-amino acid cytoplasmic domain. The cysteine-rich region contains the nerve growth factor binding domain.

In the current study, the investigators used a protein, p45, known to stimulate nervous system regeneration in lower animals but lacking in humans. They found that when added to cultures of human neurons, p45 markedly interfered with the function of p75 as a co-receptor for NgR. p45 bound p75 through both its transmembrane (TM) domain and death domain (DD).

To understand the underlying mechanisms, they determined the three-dimensional NMR solution structure of the intracellular domain of p45 and characterized its interaction with p75. They identified the residues involved in this interaction by NMR and co-immunoprecipitation.

Results of these structural and functional studies published in the August 5, 2014, online edition of the journal PLOS Biology revealed that p45 bound specifically to conserved regions in the p75 transmembrane domain and in the intracellular domain and that this binding blocked p75 dimerization along with its downstream signaling. Blocking the activity of p75 allowed nervous tissue to regenerate.

“This research implies that we might be able to mimic neuronal repair processes that occur naturally in lower animals, which would be very exciting,” said senior author Dr. Kuo-Fen Lee, professor of molecular neurobiology at the Salk Institute for Biological Studies. “We do not know why this nerve regeneration does not occur in humans. We can speculate that the brain has so many neural connections that this regeneration is not absolutely necessary.”

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Salk Institute for Biological Studies