PXD071594-1

PXD071594 is an original dataset announced via ProteomeXchange.

Title	LRRK2G2019S acts as a dominant interfering mutant in the context 1 of iron overload
Description	A key pathological feature of Parkinson’s Disease (PD) is the loss of neuromelanin, an iron chelator within the dopaminergic neurons, which results in iron toxicity thought to result in selective neuronal vulnerability. This implicated iron handling pathways as an early target of research in PD. Given the critical role of PD-related activating mutations in LRRK2 (leucine-rich repeat protein kinase 2) within membrane trafficking pathways we examined the impact of mutant LRRK2G2019S on iron homeostasis within a model macrophage cell line known to have high iron capacity. Proteomics analysis revealed a dysregulation of iron-related proteins in steady state with highly elevated levels of ferritin light chain and a reduction of ferritin heavy chain. LRRK2 mutant cells showed efficient ferritinophagy upon iron chelation, but upon iron overload there was a near complete block in the degradation of the ferritinophagy adaptor NCOA4. Surprisingly, NCOA4 levels were not rescued upon inhibition of the LRRK2 kinase activity in iron overload conditions, nor was the phosphorylation of substrate Rab GTPases. We therefore generated a CRISPR mutation to delete the kinase domain of LRRK2 and express only the Rab-binding armadillo repeat domain. Although the kinase domain was deleted, the truncation mutant of LRRK2 showed strong Rab8 phosphorylation in conditions of iron overload, similar to LRRK2G2019S cells, with the phosphorylated Rab8 accumulating at the plasma membrane. These data indicate that the G2019S mutation acts as a kinase independent, dominant-interfering mutant specifically in conditions of iron overload. Together, our data implicate LRRK2 as a key regulator of iron homeostasis and point to the need for an increased focus on the mechanisms of iron dysregulation in PD.
HostingRepository	PRIDE
AnnounceDate	2026-04-27
AnnouncementXML	Submission_2026-04-27_11:49:23.407.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD071594
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Eric Bonneil
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	monohydroxylated residue; deamidated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-04 15:01:10	ID requested
⏵ 1	2026-04-27 11:49:23	announced

10.6019/PXD071594;

submitter keyword: Parkinson's Disease, proteomics,LRRK2

Michel Desjardins
contact affiliation	Université de Montréal
contact email	michel.desjardins@umontreal.ca
lab head
Eric Bonneil
contact affiliation	Proteomic Platform
contact email	eric.bonneil@umontreal.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD071594
     1. Label: PRIDE project
     2. Name: LRRK2G2019S acts as a dominant interfering mutant in the context 1 of iron overload