Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration
Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of Pten knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic n...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/88279 |
| _version_ | 1797658927798681600 |
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| author | Marco Leibinger Charlotte Zeitler Miriam Paulat Philipp Gobrecht Alexander Hilla Anastasia Andreadaki Rainer Guthoff Dietmar Fischer |
| author_facet | Marco Leibinger Charlotte Zeitler Miriam Paulat Philipp Gobrecht Alexander Hilla Anastasia Andreadaki Rainer Guthoff Dietmar Fischer |
| author_sort | Marco Leibinger |
| collection | DOAJ |
| description | Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of Pten knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and Pten knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine CNS neurons and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) facilitates axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries. |
| first_indexed | 2024-03-11T18:06:30Z |
| format | Article |
| id | doaj.art-ba03f88517c04c51a9fe454aa6c3094c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T18:06:30Z |
| publishDate | 2023-10-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-ba03f88517c04c51a9fe454aa6c3094c2023-10-17T06:30:42ZengeLife Sciences Publications LtdeLife2050-084X2023-10-011210.7554/eLife.88279Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regenerationMarco Leibinger0https://orcid.org/0000-0001-6618-324XCharlotte Zeitler1https://orcid.org/0000-0003-2318-2890Miriam Paulat2Philipp Gobrecht3Alexander Hilla4Anastasia Andreadaki5Rainer Guthoff6Dietmar Fischer7https://orcid.org/0000-0002-1816-3014Center for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, GermanyCenter for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, GermanyDepartment of Cell Physiology, Ruhr University of Bochum, Bochum, GermanyCenter for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, GermanyDepartment of Cell Physiology, Ruhr University of Bochum, Bochum, GermanyCenter for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, GermanyEye Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, GermanyCenter for Pharmacology, Institute II, Medical Faculty and University of Cologne, Cologne, Germany; Department of Cell Physiology, Ruhr University of Bochum, Bochum, GermanyInjured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of Pten knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and Pten knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine CNS neurons and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) facilitates axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries.https://elifesciences.org/articles/88279axon regenerationspinal cord injuryoptic nerve injuryparthenolidemicrotuble detyrosination |
| spellingShingle | Marco Leibinger Charlotte Zeitler Miriam Paulat Philipp Gobrecht Alexander Hilla Anastasia Andreadaki Rainer Guthoff Dietmar Fischer Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration eLife axon regeneration spinal cord injury optic nerve injury parthenolide microtuble detyrosination |
| title | Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration |
| title_full | Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration |
| title_fullStr | Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration |
| title_full_unstemmed | Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration |
| title_short | Inhibition of microtubule detyrosination by parthenolide facilitates functional CNS axon regeneration |
| title_sort | inhibition of microtubule detyrosination by parthenolide facilitates functional cns axon regeneration |
| topic | axon regeneration spinal cord injury optic nerve injury parthenolide microtuble detyrosination |
| url | https://elifesciences.org/articles/88279 |
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