PXD024898

PXD024898 is an original dataset announced via ProteomeXchange.

Title	R1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils
Description	Gain-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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:32:24.395.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Raja Sekhar Nirujogi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-22 00:57:38	ID requested
1	2022-02-16 14:20:54	announced
⏵ 2	2024-10-22 05:32:29	announced	2024-10-22: Updated project metadata.

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;

submitter keyword: Parkinsosn's disease, PRM,LRRK2, Rab-GTPase

Esther Sammler
contact affiliation	Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, DD1 5EH, UK.
contact email	e.m.sammler@dundee.ac.uk
lab head
Raja Sekhar Nirujogi
contact affiliation	MRC Protein Phosphorylation Unit, university of Dundee
contact email	rnirujogi@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024898
     1. Label: PRIDE project
     2. Name: R1441G but not G201S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils