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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
|
| _version_ | 1797111156624588800 |
|---|---|
| author | Ribas, VT Vahsen, BF Tatenhorst, L Estrada, V Dambeck, V Almeida, RA Bähr, M Michel, U Koch, JC Müller, HW Lingor, P |
| author_facet | Ribas, VT Vahsen, BF Tatenhorst, L Estrada, V Dambeck, V Almeida, RA Bähr, M Michel, U Koch, JC Müller, HW Lingor, P |
| author_sort | Ribas, VT |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-07T08:04:48Z |
| format | Journal article |
| id | oxford-uuid:37087988-cefe-4816-9715-2dd0438b0867 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:04:48Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:37087988-cefe-4816-9715-2dd0438b08672023-10-27T07:21:26ZAAV-mediated inhibition of ULK1 promotes axonal regeneration in the central nervous system in vitro and in vivoJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:37087988-cefe-4816-9715-2dd0438b0867EnglishSymplectic ElementsSpringer Nature2021Ribas, VTVahsen, BFTatenhorst, LEstrada, VDambeck, VAlmeida, RABähr, MMichel, UKoch, JCMüller, HWLingor, PAxonal 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. |
| spellingShingle | Ribas, VT Vahsen, BF Tatenhorst, L Estrada, V Dambeck, V Almeida, RA Bähr, M Michel, U Koch, JC Müller, HW Lingor, P 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 |
| work_keys_str_mv | AT ribasvt aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT vahsenbf aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT tatenhorstl aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT estradav aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT dambeckv aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT almeidara aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT bahrm aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT michelu aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT kochjc aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT mullerhw aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo AT lingorp aavmediatedinhibitionofulk1promotesaxonalregenerationinthecentralnervoussysteminvitroandinvivo |