RESUMO

Axonal damage is an early step in traumatic and neurodegenerative disorders of the central nervous system (CNS). Damaged axons are not able to regenerate sufficiently in the adult mammalian CNS, leading to permanent neurological deficits. Recently, we showed that inhibition of the autophagic protein ULK1 promotes neuroprotection in different models of neurodegeneration. Moreover, we demonstrated previously that axonal protection improves regeneration of lesioned axons. However, whether axonal protection mediated by ULK1 inhibition could also improve axonal regeneration is unknown. Here, we used an adeno-associated viral (AAV) vector to express a dominant-negative form of ULK1 (AAV.ULK1.DN) and investigated its effects on axonal regeneration in the CNS. We show that AAV.ULK1.DN fosters axonal regeneration and enhances neurite outgrowth in vitro. In addition, AAV.ULK1.DN increases neuronal survival and enhances axonal regeneration after optic nerve lesion, and promotes long-term axonal protection after spinal cord injury (SCI) in vivo. Interestingly, AAV.ULK1.DN also increases serotonergic and dopaminergic axon sprouting after SCI. Mechanistically, AAV.ULK1.DN leads to increased ERK1 activation and reduced expression of RhoA and ROCK2. Our findings outline ULK1 as a key regulator of axonal degeneration and regeneration, and define ULK1 as a promising target to promote neuroprotection and regeneration in the CNS.

Assuntos

Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Axônios/metabolismo , Dependovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos , Regeneração Nervosa , Traumatismos do Nervo Óptico/terapia , Nervo Óptico/metabolismo , Traumatismos da Medula Espinal/terapia , Medula Espinal/metabolismo , Animais , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Axônios/patologia , Células Cultivadas , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Regulação para Baixo , Feminino , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Crescimento Neuronal , Nervo Óptico/patologia , Traumatismos do Nervo Óptico/genética , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/patologia , Ratos Wistar , Neurônios Serotoninérgicos/metabolismo , Neurônios Serotoninérgicos/patologia , Medula Espinal/patologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Fatores de Tempo , Proteínas rho de Ligação ao GTP/metabolismo , Quinases Associadas a rho/metabolismo