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AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo

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...

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Autores principales: Ribas, Vinicius Toledo, Vahsen, Björn Friedhelm, Tatenhorst, Lars, Estrada, Veronica, Dambeck, Vivian, Almeida, Raquel Alves, Bähr, Mathias, Michel, Uwe, Koch, Jan Christoph, Müller, Hans Werner, Lingor, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910615/
https://www.ncbi.nlm.nih.gov/pubmed/33637688
http://dx.doi.org/10.1038/s41419-021-03503-3
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author Ribas, Vinicius Toledo
Vahsen, Björn Friedhelm
Tatenhorst, Lars
Estrada, Veronica
Dambeck, Vivian
Almeida, Raquel Alves
Bähr, Mathias
Michel, Uwe
Koch, Jan Christoph
Müller, Hans Werner
Lingor, Paul
author_facet Ribas, Vinicius Toledo
Vahsen, Björn Friedhelm
Tatenhorst, Lars
Estrada, Veronica
Dambeck, Vivian
Almeida, Raquel Alves
Bähr, Mathias
Michel, Uwe
Koch, Jan Christoph
Müller, Hans Werner
Lingor, Paul
author_sort Ribas, Vinicius Toledo
collection PubMed
description 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.
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spelling pubmed-79106152021-03-04 AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo Ribas, Vinicius Toledo Vahsen, Björn Friedhelm Tatenhorst, Lars Estrada, Veronica Dambeck, Vivian Almeida, Raquel Alves Bähr, Mathias Michel, Uwe Koch, Jan Christoph Müller, Hans Werner Lingor, Paul Cell Death Dis Article 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. Nature Publishing Group UK 2021-02-26 /pmc/articles/PMC7910615/ /pubmed/33637688 http://dx.doi.org/10.1038/s41419-021-03503-3 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ribas, Vinicius Toledo
Vahsen, Björn Friedhelm
Tatenhorst, Lars
Estrada, Veronica
Dambeck, Vivian
Almeida, Raquel Alves
Bähr, Mathias
Michel, Uwe
Koch, Jan Christoph
Müller, Hans Werner
Lingor, Paul
AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo
title AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo
title_full AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo
title_fullStr AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo
title_full_unstemmed AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo
title_short AAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivo
title_sort aav-mediated inhibition of ulk1 promotes axonal regeneration in the central nervous system in vitro and in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910615/
https://www.ncbi.nlm.nih.gov/pubmed/33637688
http://dx.doi.org/10.1038/s41419-021-03503-3
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