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

Vahsen, B. F., Ribas, V. T., Sundermeyer, J., Boecker, A., Dambeck, V., Lenz, C., et al. (2020). Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing. Cell Death and Differentiation, In Press. doi:10.1038/s41418-020-0543-y.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-D3ED-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-D3F3-9
Genre: Journal Article

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 Creators:
Vahsen, B. F., Author
Ribas, V. T., Author
Sundermeyer, J., Author
Boecker, A., Author
Dambeck, V., Author
Lenz, C.1, Author              
Shomroni, O., Author
Gomes, L. C., Author
Tatenhorst, L., Author
Barski, E., Author
Roser, A.-E., Author
Michel, U., Author
Urlaub, H.2, Author              
Salinas, G., Author
Bähr, M., Author
Koch, J. C., Author
Lingor, P., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              
2Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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Free keywords: Experimental models of disease; Neurological disorders; Neuroscience; Translational research
 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 Kif1b and Ddit3. 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.

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Language(s): eng - English
 Dates: 2020-04-27
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41418-020-0543-y
 Degree: -

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Title: Cell Death and Differentiation
Source Genre: Journal
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Pages: 18 Volume / Issue: - Sequence Number: In Press Start / End Page: - Identifier: -