title: Myelin Lipids Inhibit Axon Regeneration Following Spinal Cord Injury: a Novel Perspective for Therapy.
abstract: Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory environment of the injury site, i.e., to chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs). Here, we used shiverer (shi) mice to assess axon regeneration following spinal cord injury in the presence of MAIs and CSPG but in the absence of compact myelin. Although in vitro shi neurons displayed a similar intrinsic neurite outgrowth to wild-type neurons, in vivo, shi fibers had increased regenerative capacity, suggesting that the wild-type spinal cord contains additional inhibitors besides MAIs and CSPG. Our data show that besides myelin protein, myelin lipids are highly inhibitory for neurite outgrowth and suggest that this inhibitory effect is released in the shi spinal cord given its decreased lipid content. Specifically, we identified cholesterol and sphingomyelin as novel myelin-associated inhibitors that operate through a Rho-dependent mechanism and have inhibitory activity in multiple neuron types. We further demonstrated the inhibitory action of myelin lipids in vivo, by showing that delivery of 2-hydroxypropyl-β-cyclodextrin, a drug that reduces the levels of lipids specifically in the injury site, leads to increased axon regeneration of wild-type (WT) dorsal column axons following spinal cord injury. In summary, our work shows that myelin lipids are important modulators of axon regeneration that should be considered together with protein MAIs as critical targets in strategies aiming at improving axonal growth following injury.
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar-ICBAS, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
authors.forename: Fernando M
authors.initials: FM
authors.lastname: Mar
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar-ICBAS, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: da Silva
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: Marlene M
authors.initials: MM
authors.lastname: Morgado
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.|Lysosome and Peroxisome Biology group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: Lorena G
authors.initials: LG
authors.lastname: Rodrigues
authors.affiliation: Lysosome and Peroxisome Biology group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodrigues
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: Marta I L
authors.initials: MIL
authors.lastname: Pereira
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Marques
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar-ICBAS, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
authors.forename: Vera F
authors.initials: VF
authors.lastname: Sousa
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Coentro
authors.affiliation: Lysosome and Peroxisome Biology group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: Clara
authors.initials: C
authors.lastname: Sá-Miranda
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal. msousa@ibmc.up.pt.
authors.forename: Mónica M
authors.initials: MM
authors.lastname: Sousa
authors.affiliation: Nerve Regeneration group, Instituto de Biologia Molecular e Celular-IBMC, University of Porto, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Brites
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001369:Axons / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008810:Mice, Inbred C57BL; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D013109:Sphingomyelins / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000628:therapy*; D047392:beta-Cyclodextrins / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D008055:Lipids; D013109:Sphingomyelins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol; D020741:rho GTP-Binding Proteins
keywords: Axon regeneration; Cholesterol; Myelin lipid; Shiverer mice; Sphingomyelin; Spinal cord injury