AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo
| Autor: | Vinicius Toledo, Ribas, Björn Friedhelm, Vahsen, Lars, Tatenhorst, Veronica, Estrada, Vivian, Dambeck, Raquel Alves, Almeida, Mathias, Bähr, Uwe, Michel, Jan Christoph, Koch, Hans Werner, Müller, Paul, Lingor |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
rho GTP-Binding Proteins
Time Factors Genetic Vectors Neuronal Outgrowth Cell death in the nervous system Down-Regulation Spinal cord injury Article Animals Autophagy-Related Protein-1 Homolog Rats Wistar Neurodegeneration lcsh:QH573-671 Cells Cultured Spinal Cord Injuries rho-Associated Kinases Mitogen-Activated Protein Kinase 3 lcsh:Cytology Dopaminergic Neurons Gene Transfer Techniques Optic Nerve Dependovirus Axons Nerve Regeneration Disease Models Animal Spinal Cord nervous system Optic Nerve Injuries Female Serotonergic Neurons |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 2, Pp 1-18 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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