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PXD024898

PXD024898 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleR1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils
DescriptionGain-of kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause Parkinson’s disease (PD), albeit with incomplete and age-dependent penetrance, offering the prospect of disease-modifying treatment strategies via LRRK2 kinase inhibition. LRRK2 phosphorylates a subgroup of RabGTPases including Rab10 and pathogenic mutations enhance LRRK2-mediated phosphorylation of Rab10 at Thr73. In this study we analyse LRRK2 dependent Rab10Thr73 phosphorylation in human peripheral blood neutrophils isolated from 101 individuals using quantitative immunoblotting and mass spectrometry. Our cohort includes 42 LRRK2 mutation carriers (21 with the G2019S mutation that resides in the kinase domain and 21 with the R1441G mutation that lies within the ROC-COR domain), 27 patients with idiopathic PD, and 32 controls. We show that LRRK2 dependent Rab10 Thr73 phosphorylation is significantly elevated in all R1441G LRRKR2 mutation carriers irrespective of disease status. PD manifesting and non-manifesting G2019S mutation carriers as well as idiopathic PD samples did not display elevated Rab10 Thr73 phosphorylation. Furthermore, we analysed brain samples of 10 G2019S and 1 R1441H mutation carriers as well as 10 individuals with idiopathic PD and 10 controls. We find high variability for pRab10Thr73 phosphorylation amongst donors irrespective of genetic and disease state. We conclude that in vivo LRRK2 dependent pRab10Thr73 analysis in human peripheral blood neutrophils is a specific and robust biomarker for LRRK2 kinase activation for individuals with mutations such as R1441G that enhance pRab10Thr73 phosphorylation over 2-fold. We provide the first evidence that the LRRK2 R1441G mutation enhances LRRK2 kinase activity in a primary human cell.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_05:32:24.395.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterRaja Sekhar Nirujogi
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListphosphorylated residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-03-22 00:57:38ID requested
12022-02-16 14:20:54announced
22024-10-22 05:32:29announced2024-10-22: Updated project metadata.
Publication List
Fan Y, Nirujogi RS, Garrido A, Ruiz-Mart, í, nez J, Bergareche-Yarza A, Mondrag, ó, n-Rezola E, Vinagre-Arag, ó, n A, Croitoru I, Gorostidi Pagola A, Paternain Markinez L, Alcalay R, Hickman RA, D, ü, ring J, Gomes S, Pratuseviciute N, Padmanabhan S, Valldeoriola F, P, é, rez Sisqu, é, s L, Malagelada C, Ximelis T, Molina Porcel L, Mart, í MJ, Tolosa E, Alessi DR, Sammler EM, R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils. Acta Neuropathol, 142(3):475-494(2021) [pubmed]
10.1007/s00401-021-02325-z;
Keyword List
submitter keyword: Parkinsosn's disease, PRM,LRRK2, Rab-GTPase
Contact List
Esther Sammler
contact affiliationMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, DD1 5EH, UK.
contact emaile.m.sammler@dundee.ac.uk
lab head
Raja Sekhar Nirujogi
contact affiliationMRC Protein Phosphorylation Unit, university of Dundee
contact emailrnirujogi@dundee.ac.uk
dataset submitter
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