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PXD021945 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleSpastin recovery in hereditary spastic paraplegia by preventing neddylation-dependent degradation
DescriptionHereditary 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.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterMarialuisa Casella
SpeciesList scientific name: Bos taurus (Bovine); NCBI TaxID: 9913; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
Dataset History
RevisionDatetimeStatusChangeLog Entry
02020-10-13 02:48:54ID requested
12020-10-22 05:20:12announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: spastin, HIPK2, SPG4-HSP, Ubiquitination, protesomal degradation
Contact List
Marco Crescenzi
contact affiliationIstituto Superiore di Sanità
contact emailmarco.crescenzi@iss.it
lab head
Marialuisa Casella
contact affiliationIstituto Superiore di Sanità
contact emailmarialuisa.casella@iss.it
dataset submitter
Full Dataset Link List
Dataset FTP location
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