PXD035566

PXD035566 is an original dataset announced via ProteomeXchange.

Title	Loss of NDR1/2 kinases impairs endomembrane trafficking and ATG9A localisation, reduces autophagy and leads to neurodegeneration
Description	Autophagy is essential for neuronal development and its deregulation contributes to neurodegenerative diseases. NDR1 and NDR2 are highly conserved kinases implicated in neuronal development, mitochondrial health and autophagy, but how they affect mammalian brain development in vivo is not known. Using single and double Ndr1/2 knockout mouse models we show that, dual, but not individual loss of Ndr1/2 in neurons causes neurodegeneration during brain development, but also in adult mice. Proteomic and phosphoproteomic comparisons between Ndr1/2 knockout and control brains revealed novel kinase substrates and indicated that endocytosis is significantly affected in the absence of NDR1/2. We validated the endocytic protein, Raph1/Lpd1 as a novel NDR1/2 substrate and showed that both NDR1/2 and Raph1 are critical for endocytosis and membrane recycling. In NDR1/2 knockout brains, we observed prominent accumulation of transferrin receptor, p62 and ubiquitinated proteins, indicative of a major impairment of protein homeostasis. Furthermore, the levels of LC3-positive autophagosomes were reduced in knockout neurons, implying that reduced autophagy efficiency mediates p62 accumulation and neurotoxicity. Mechanistically, pronounced mislocalisation of the transmembrane autophagy protein ATG9A at the neuronal periphery, impaired axonal ATG9A trafficking and increased ATG9A surface levels further confirm defects in membrane trafficking and could underlie the impairment in autophagy. We provide novel insight into the roles of NDR1/2 kinases in maintaining neuronal health.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:57:28.195.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Simeon Mihaylov
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-25 02:12:29	ID requested
1	2022-11-21 00:40:29	announced
⏵ 2	2023-11-14 08:57:28	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: autophagy,NDR1/2, ATG9A, neurodegeneration

Sila K. Ultanir
contact affiliation	Kinases and Brain Development Laboratory, The Francis Crick Institute, London, UK
contact email	sila.ultanir@crick.ac.uk
lab head
Simeon Mihaylov
contact affiliation	The Francis Crick Institute
contact email	simeon.mihaylov@crick.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035566
     1. Label: PRIDE project
     2. Name: Loss of NDR1/2 kinases impairs endomembrane trafficking and ATG9A localisation, reduces autophagy and leads to neurodegeneration