No abstract

Nature Reviews publishes timely, authoritative articles that are of broad interest and exceptional quality. Thank you for taking the time to help us to ensure that our articles meet these high standards.Review articles in Nature Reviews journals provide accessible, authoritative and balanced overviews of a field or topic. These articles are targeted towards readers from advanced undergraduate level and upwards, including researchers, academics and clinicians, and should be accessible to readers working in any discipline.Please submit your report in narrative form and provide detailed justifications for all statements. Confidential comments to the editor are welcome, but it is helpful if the main points are stated in the comments for transmission to the authors.Please note that all Nature Reviews articles will be thoroughly edited before publication and all figures will be redrawn by our in-house art editors. We therefore request that you concentrate on the scientific content of the article, rather than any minor errors in language or grammar. Please consider and comment on the following points when reviewing this manuscript:• Is the article timely and does it provide a useful addition to the existing literature?• Are the scope and aims of the article clear?• Are the ideas logically presented and discussed?• Is the article accessible to a wide audience, including readers who are not specialists in your own field?• Does the article provide a balanced overview of the literature? Please bear in mind that it may not be possible to cover all aspects of a field within such a concise article.• Does the article provide new insight into recent advances?• Is the discussion fair and accurate? Although our authors are encouraged to be opinionated, they should not ignore alternative points of view.• Do the figures, boxes and tables provide clear and accurate information? Are there any additional or alternative display items that you think that the authors should include?• Are the references appropriate and up-to-date? Do they reflect the scope of the article?• Are you aware of any undeclared conflicts of interest that might affect the balance, or perceived balance, of the article?

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.

No abstract