PXD057308-1

PXD057308 is an original dataset announced via ProteomeXchange.

Title	Urinary proteome profiling in rats and humans unveils biomarkers of LRRK2 kinase activity in Parkinson's disease
Description	Pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD) and often lead to increased kinase activity, making LRRK2 inhibitors promising treatment options. However, despite ongoing clinical trials, specific, sensitive, and non-invasive biomarkers for measuring drug target engagement or stratifying mutation carriers remain elusive. Analyzing urinary proteome profiles of 1,214 individuals with PD and/or LRRK2 mutations across three cohorts, we identified 177 significantly altered urinary proteins linked to dysregulation of immune system processes, membrane trafficking and lysosomal-glycosphingolipid metabolism in pathogenic LRRK2 carriers. Machine learning narrowed these features down to a cohort-agnostic panel of 30 key urinary proteins -primarily associated with lysosomal dysfunction- that serve as a robust readout of LRRK2 activity. Our model excelled in classifying mutation status, achieving a ROC AUC of 91%, 84% sensitivity, and 85% specificity. Additionally, urinary proteome profiling of knockout and G2019S Lrrk2 rats, along with those treated with two potent LRRK2 inhibitors, validated the utility of this urinary protein panel for assessing the pharmacodynamic response to LRRK2 inhibitors in clinic. Together, our urinary biomarker candidates for assessing LRRK2 hyperactivation and inhibition will be vital for supporting current and future therapeutic strategies focused on restoring LRRK2's normal physiological function in PD.
HostingRepository	PRIDE
AnnounceDate	2026-01-22
AnnouncementXML	Submission_2026-01-22_02:14:35.744.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: NEWT:10116;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-29 12:56:45	ID requested
⏵ 1	2026-01-22 02:14:36	announced

Dataset with its publication pending

submitter keyword: Urine, Parkinson's Disease, proteomics

Matthias Mann
contact affiliation	Department of Proteomics and Signal Transduction Max Planck Institute of Biochemistry
contact email	mmann@biochem.mpg.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD057308
     1. Label: PRIDE project
     2. Name: Urinary proteome profiling in rats and humans unveils biomarkers of LRRK2 kinase activity in Parkinson's disease