PXD019335

PXD019335 is an original dataset announced via ProteomeXchange.

Title	A new Knock-in mouse model of SCA14 with increased PKCγ activity induces a SCA-like phenotype with perturbed Purkinje cell maturation and ataxic motor behavior
Description	Spinocerebellar ataxias (SCAs) are a group of cerebellar diseases characterized by loss and dysfunction of Purkinje cells and Spinocerebellar ataxia type 14 (SCA14) is caused by missense mutations or deletions in the Protein kinase C γ (PKCγ) gene. Until now, more than 40 different mutations or deletions in the PKCγ gene have been found in SCA14 patients. Many of these mutations have been shown to have an increased enzymatic activity in cell-based assays, but there is also evidence that the mutations may result in inefficient activation of downstream signalling pathways compatible with a loss of function. Therefore, it is still unclear how mutant PKCγ may cause the disease. We have previously generated a transgenic SCA14 mouse model with a human SCA14 mutation in the kinase domain. This transgenic mouse shows mild ataxia and abnormal Purkinje cell dendritic development with a morphology indistinguishable from that of PKC activator treated Purkinje cells, indicating that the PKCγ with this kinase domain mutation has indeed increased biological activity. In order to confirm that increased PKC activity in vivo perturbs Purkinje cell maturation and induces ataxia we have now created a new knock-in mouse model with a missense mutation in the PKCγ pseudosubstrate domain keeping the PKCγ protein in the open active conformation. This knock-in mouse shows indeed abnormal Purkinje cell maturation and ataxia, even in a heterozygous state corresponding to the human disease situation. Our findings confirm that constitutive activation of PKCγ is one way to induce a phenotype corresponding to human spinocerebellar ataxia.
HostingRepository	PRIDE
AnnounceDate	2022-02-24
AnnouncementXML	Submission_2022-02-24_04:36:41.270.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD019335
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Alexander Schmidt
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	Phospho; TMT6plex; phosphorylated residue; Oxidation; Acetyl; Carbamidomethyl
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-05-21 22:46:53	ID requested
⏵ 1	2022-02-24 04:36:42	announced

Shimobayashi E, Kapfhammer JP, Shows Perturbed Purkinje Cell Maturation and Ataxic Motor Behavior. J Neurosci, 41(9):2053-2068(2021) [pubmed]

submitter keyword: SCA, PKC gamma, Phosphoproteomics

Alexander Schmidt
contact affiliation	Proteomics Core Facility, Biozentrum, University of Basel, Switzerland
contact email	alex.schmidt@unibas.ch
lab head
Alexander Schmidt
contact affiliation	Proteomics Core Facility
contact email	alex.schmidt@unibas.ch
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019335
     1. Label: PRIDE project
     2. Name: A new Knock-in mouse model of SCA14 with increased PKCγ activity induces a SCA-like phenotype with perturbed Purkinje cell maturation and ataxic motor behavior