A small peptide mimetic of brain-derived neurotrophic factor promotes peripheral myelination.
The expression of the neurotrophins and their receptors is essential for peripheral nervous system development and myelination. We have previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts contrasting influences upon Schwann cell myelination in vitro - promoting myelination via neuronally expressed p75NTR, but inhibiting myelination via neuronally expressed TrkB. We have generated a small peptide called cyclo-dPAKKR that structurally mimics the region of BDNF that binds p75NTR. Here, we have investigated whether utilizing cyclo-dPAKKR to selectively target p75NTR is an approach that could exert a unified promyelinating response. Like BDNF, cyclo-dPAKKR promoted myelination of nerve growth factor-dependent neurons in vitro, an effect dependent on the neuronal expression of p75NTR. Importantly, cyclo-dPAKKR also significantly promoted the myelination of tropomyosin-related kinase receptor B-expressing neurons in vitro, whereas BDNF exerted a significant inhibitory effect. This indicated that while BDNF exerted a contrasting influence upon the myelination of distinct subsets of dorsal root ganglion (DRG) neurons in vitro, cyclo-dPAKKR uniformly promoted their myelination. Local injection of cyclo-dPAKKR adjacent to the developing sciatic nerve in vivo significantly enhanced myelin protein expression and significantly increased the number of myelinated axons. These results demonstrate that cyclo-dPAKKR promotes peripheral myelination in vitro and in vivo, suggesting it is a strategy worthy of further investigation for the treatment of peripheral demyelinating diseases.
Department of Anatomy and Neuroscience, The University of Melbourne, Victoria, Australia. xiaoj@unimelb.edu.au
Junhua
J
Xiao
Richard A
RA
Hughes
Joe Y
JY
Lim
Agnes W
AW
Wong
Jason J
JJ
Ivanusic
Anita H
AH
Ferner
Trevor J
TJ
Kilpatrick
Simon S
SS
Murray
D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D020880:Neuregulins; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency; D012583:Schwann Cells; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D047908:Intracellular Signaling Peptides and Proteins; D020880:Neuregulins; C108113:Nrg3 protein, mouse; D010455:Peptides; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse