PXD021945

PXD021945 is an original dataset announced via ProteomeXchange.

Title	Spastin recovery in hereditary spastic paraplegia by preventing neddylation-dependent degradation
Description	Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disease most commonly caused by autosomal dominant mutations in the SPG4 gene encoding the microtubule severing protein spastin. We hypothesise that SPG4-HSP is attributable to reduced spastin function due to haploinsufficiency, thus therapeutic approaches which elevate levels of the wild type spastin allele may be an effective therapy. However until now, how spastin levels are regulated is largely unknown. Here, we show that the kinase HIPK2 regulates spastin protein levels in proliferating cells, in differentiated neurons and in vivo. Our work reveals that HIPK2-mediated phosphorylation of spastin at S268 inhibits spastin K48-poly-ubiquitination at K554 and prevents its neddylation-dependent proteasomal degradation. In a spastin RNAi neuronal cell model, overexpression of HIPK2, or inhibition of neddylation, restores spastin levels and rescues neurite defects. Notably, we demonstrate that spastin levels can be restored pharmacologically by inhibiting its neddylation-mediated degradation in neurons derived from a spastin mouse model of HSP and in patient derived cells, thus revealing novel therapeutic targets for the treatment of SPG4-HSP. We do not know how S268 phosphorylation prevents spastin ubiquitination at K554; we hypothesised that phosphorylation can protect spastin from polyubiquitination by impairing the recruitment of proteins belonging to ubiquitination pathway or by promoting the interactions with factors that mask spastin region necessary for efficient ubiquitination/degradation. To have insight about these hypotheses, we analysed by mass spectrometry (MS) the interactome of spastin-S268A and -S268D upon overexpression in HeLa cells.
HostingRepository	PRIDE
AnnounceDate	2020-10-22
AnnouncementXML	Submission_2020-10-22_05:20:12.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marialuisa Casella
SpeciesList	scientific name: Bos taurus (Bovine); NCBI TaxID: 9913; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ

Revision	Datetime	Status	ChangeLog Entry
0	2020-10-13 02:48:54	ID requested
⏵ 1	2020-10-22 05:20:12	announced

Dataset with its publication pending

submitter keyword: spastin, HIPK2, SPG4-HSP, Ubiquitination, protesomal degradation

Marco Crescenzi
contact affiliation	Istituto Superiore di Sanità
contact email	marco.crescenzi@iss.it
lab head
Marialuisa Casella
contact affiliation	Istituto Superiore di Sanità
contact email	marialuisa.casella@iss.it
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/2020/10/PXD021945

PRIDE project URI

• PRIDE
  1. PXD021945
     1. Label: PRIDE project
     2. Name: Spastin recovery in hereditary spastic paraplegia by preventing neddylation-dependent degradation