PXD011862

PXD011862 is an original dataset announced via ProteomeXchange.

Title	Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing
Description	Several traumatic and neurodegenerative disorders of the CNS show axonal degeneration as a key and early pathological feature. Following a focal axonal lesion, an extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, activation of autophagic proteins, including Unc-51 like autophagy activating kinase 1 (ULK1), has been shown but its role is incompletely understood. Here, we overexpressed a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons in vitro and in the spinal cord (SC) and optic nerve (ON) in vivo. We found a significant inhibitory effect on autophagy in vitro and in vivo. While no effect on cell survival could be observed, ULK1.DN attenuated AAD after axotomy in microfluidic chambers in vitro. Models of SC injury and ON crush in vivo confirmed an attenuation of axonal degeneration by ULK1.DN. In a translational approach, we employed the selective ULK1 inhibitor SBI-0206965 (SBI) and found an attenuation of AAD after ON crush in vivo mediated by a reduction of autophagy by SBI. Quantitative proteomic profiling after ULK1.DN overexpression in vitro revealed a regulation of proteins associated with translation and splicing. A differential exon expression analysis then identified the genes kinesin family member 1B (Kif1b), DNA damage inducible transcript 3 (Ddit3) and WD repeat domain 6 (Wdr6) as targets of ULK1.DN and potential mediators of its degeneration-attenuating effect. These findings reveal ULK1 as an important mediator of axonal degeneration and elucidate its function in splicing, defining it as a putative therapeutic target.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:03:02.660.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christof Lenz
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	No PTMs are included in the dataset
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2018-11-28 01:20:53	ID requested
1	2020-04-30 07:49:25	announced
⏵ 2	2024-10-22 05:03:04	announced	2024-10-22: Updated project metadata.

Vahsen BF, Ribas VT, Sundermeyer J, Boecker A, Dambeck V, Lenz C, Shomroni O, Caldi Gomes L, Tatenhorst L, Barski E, Roser AE, Michel U, Urlaub H, Salinas G, B, ä, hr M, Koch JC, Lingor P, Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing. Cell Death Differ, 27(10):2810-2827(2020) [pubmed]

10.1038/s41418-020-0543-y;

curator keyword: Biological, Biomedical

submitter keyword: autophagy/ axonal degeneration/ ULK1/ spinal cord/ optic nerve/ splicing

Christof Lenz
contact affiliation	Max Planck Institute for Biophysical Chemistry; University Medical Center Goettingen
contact email	christof.lenz@mpibpc.mpg.de
lab head
Christof Lenz
contact affiliation	Max Planck Institute for Biophysical Chemistry
contact email	christof.lenz@mpibpc.mpg.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/04/PXD011862

PRIDE project URI

• PRIDE
  1. PXD011862
     1. Label: PRIDE project
     2. Name: Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing