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Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing

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Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing. / Vahsen, Björn Friedhelm; Ribas, Vinicius Toledo; Sundermeyer, Jonas; Boecker, Alexander; Dambeck, Vivian; Lenz, Christof; Shomroni, Orr; Gomes, Lucas Caldi; Tatenhorst, Lars; Barski, Elisabeth; Roser, Anna-Elisa; Michel, Uwe; Urlaub, Henning; Salinas, Gabriela; Bähr, Mathias; Koch, Jan Christoph; Lingor, Paul.

In: CELL DEATH DIFFER, Vol. 27, 10.2020, p. 2810–2827.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Vahsen, BF, Ribas, VT, Sundermeyer, J, Boecker, A, Dambeck, V, Lenz, C, Shomroni, O, Gomes, LC, Tatenhorst, L, Barski, E, Roser, A-E, Michel, U, Urlaub, H, Salinas, G, Bähr, M, Koch, JC & Lingor, P 2020, 'Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing', CELL DEATH DIFFER, vol. 27, pp. 2810–2827. https://doi.org/10.1038/s41418-020-0543-y

APA

Vahsen, B. F., Ribas, V. T., Sundermeyer, J., Boecker, A., Dambeck, V., Lenz, C., Shomroni, O., Gomes, L. C., Tatenhorst, L., Barski, E., Roser, A-E., Michel, U., Urlaub, H., Salinas, G., Bähr, M., Koch, J. C., & Lingor, P. (2020). Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing. CELL DEATH DIFFER, 27, 2810–2827. https://doi.org/10.1038/s41418-020-0543-y

Vancouver

Vahsen BF, Ribas VT, Sundermeyer J, Boecker A, Dambeck V, Lenz C et al. Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing. CELL DEATH DIFFER. 2020 Oct;27:2810–2827. https://doi.org/10.1038/s41418-020-0543-y

Bibtex

@article{efa7684bb8e1423fa409bdf4b299f763,
title = "Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing",
abstract = "Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target. ",
author = "Vahsen, {Bj{\"o}rn Friedhelm} and Ribas, {Vinicius Toledo} and Jonas Sundermeyer and Alexander Boecker and Vivian Dambeck and Christof Lenz and Orr Shomroni and Gomes, {Lucas Caldi} and Lars Tatenhorst and Elisabeth Barski and Anna-Elisa Roser and Uwe Michel and Henning Urlaub and Gabriela Salinas and Mathias B{\"a}hr and Koch, {Jan Christoph} and Paul Lingor",
year = "2020",
month = oct,
doi = "10.1038/s41418-020-0543-y",
language = "English",
volume = "27",
pages = "2810–2827",
journal = "CELL DEATH DIFFER",
issn = "1350-9047",
publisher = "NATURE PUBLISHING GROUP",

}

RIS

TY - JOUR

T1 - Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing

AU - Vahsen, Björn Friedhelm

AU - Ribas, Vinicius Toledo

AU - Sundermeyer, Jonas

AU - Boecker, Alexander

AU - Dambeck, Vivian

AU - Lenz, Christof

AU - Shomroni, Orr

AU - Gomes, Lucas Caldi

AU - Tatenhorst, Lars

AU - Barski, Elisabeth

AU - Roser, Anna-Elisa

AU - Michel, Uwe

AU - Urlaub, Henning

AU - Salinas, Gabriela

AU - Bähr, Mathias

AU - Koch, Jan Christoph

AU - Lingor, Paul

PY - 2020/10

Y1 - 2020/10

N2 - Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target.

AB - Axonal degeneration is a key and early pathological feature in traumatic and neurodegenerative disorders of the CNS. Following a focal lesion to axons, extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, the accumulation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we study the effect of ULK1 inhibition in different models of lesion-induced axonal degeneration in vitro and in vivo. Overexpression of a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons attenuates axotomy-induced AAD in vitro. Both ULK1.DN and the ULK1 inhibitor SBI-0206965 protect against AAD after rat optic nerve crush in vivo. ULK1.DN additionally attenuates long-term axonal degeneration after rat spinal cord injury in vivo. Mechanistically, ULK1.DN decreases autophagy and leads to an mTOR-mediated increase in translational proteins. Consistently, treatment with SBI-0206965 results in enhanced mTOR activation. ULK1.DN additionally modulates the differential splicing of the degeneration-associated genes. These findings uncover ULK1 as an important mediator of axonal degeneration in vitro and in vivo, and elucidate its function in splicing, defining it as a putative therapeutic target.

U2 - 10.1038/s41418-020-0543-y

DO - 10.1038/s41418-020-0543-y

M3 - SCORING: Journal article

C2 - 32341448

VL - 27

SP - 2810

EP - 2827

JO - CELL DEATH DIFFER

JF - CELL DEATH DIFFER

SN - 1350-9047

ER -