Summary: New research shows a common Parkinson’s disease gene mutation causes iron to be misdirected within activated microglia, potentially contributing to neurodegeneration.
Source: PLOS
Researchers report that a prevalent genetic mutation linked to Parkinson’s disease causes iron to be mislocalized in activated microglia, according to a study published December 16 in the open-access journal PLOS Biology. The work, led by Mark Cookson at the National Institute on Aging and colleagues, highlights a cellular mechanism that could explain iron accumulation in affected brain regions and points toward targets for therapies that correct iron trafficking.
Mutations in the LRRK2 gene account for a notable fraction of Parkinson’s disease cases—approximately 5% of familial cases and about 1% of sporadic cases. LRRK2 encodes a kinase, an enzyme that modifies other proteins by adding phosphate groups, and disease-associated variants typically increase the kinase’s activity. One of LRRK2’s substrates is Rab8a, a member of the Rab family of small GTPases that regulate vesicle trafficking throughout the cell.
Rab8a contributes to the cell’s handling of iron by controlling the endocytic trafficking of the transferrin receptor: it helps internalize transferrin-bound iron and coordinates recycling of the transferrin receptor back to the cell surface after iron release. Disruption of this pathway can alter iron distribution inside cells and potentially promote oxidative damage.
To test how Parkinson’s-associated LRRK2 mutations affect Rab8a and iron handling, the authors visualized Rab8a dynamics in mouse astrocytes engineered to express pathogenic LRRK2 variants. They observed that mutant LRRK2 redirected Rab8a from its normal location in the endocytic recycling compartment and instead sequestered it at damaged lysosomes. Pharmacological inhibition of LRRK2 kinase activity reversed this mislocalization, indicating that the altered kinase activity drives the effect.
This change in Rab8a distribution had direct consequences for the transferrin receptor and iron. In cells with normal LRRK2, transferrin and its receptor were distributed across multiple endosomal compartments as expected. In contrast, cells expressing mutant LRRK2 showed clustering of transferrin and iron at the damaged lysosomes where Rab8a had been sequestered. The same pattern—mislocalization of Rab8a together with transferrin receptors—was observed in activated human microglia derived from induced pluripotent stem cells (iPSCs) carrying a pathogenic LRRK2 mutation.
Microglia are the brain’s resident immune cells and major mediators of neuroinflammation. The study extended the cell-based findings to an animal model: mice carrying the common G2019S LRRK2 mutation were exposed to a proinflammatory trigger, and researchers found increased iron accumulation within microglia in the striatum, a brain region critical for movement that is heavily affected in Parkinson’s disease. The striatal microglia also showed elevated levels of ferritin, the iron-storage protein, consistent with altered iron uptake and storage.
“Our data suggest that a key step in the pathogenesis of LRRK2 Parkinson’s disease is the interaction of the protein with Rab8a and its subsequent effect on mislocalization of iron in activated microglia,” Cookson said. Iron deposition in the brain is a well-documented feature of Parkinson’s and other neurodegenerative conditions; excess iron can promote free radical formation and mitochondrial damage, processes implicated in neuronal loss.
These results improve understanding of how enhanced LRRK2 kinase activity may contribute to Parkinson’s disease through altered intracellular trafficking and dysregulated iron handling. They also support the rationale for exploring LRRK2 kinase inhibition and related strategies as potential therapeutic approaches to prevent or reverse harmful iron accumulation in the brain.
“Our study demonstrates altered regulation of iron in Parkinson’s disease models based on the gene LRRK2,” Cookson added. “Previous work has shown that iron can be deposited in the brain; we now link this phenomenon to a known genetic cause of Parkinson’s disease and to pathways that may be targeted by new treatments.”
About this Parkinson’s disease research news
Author: Press Office
Source: PLOS
Contact: Press Office – PLOS
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Original Research: Open access.
“Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia” by Mamais A, Kluss JH, Bonet-Ponce L, Landeck N, Langston RG, Smith N, et al. PLOS Biology
Abstract
Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia
Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are also associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in cell and animal models. The small GTPase Rab8a is a LRRK2 kinase substrate and plays a role in receptor recycling and transferrin-mediated endocytic trafficking, but how PD-associated LRRK2 mutations affect Rab8a function has been unclear.
This study demonstrates that gain-of-function LRRK2 mutations cause endogenous Rab8a to be sequestered at lysosomes in cellular models, a phenotype that can be reversed by inhibiting LRRK2 kinase activity. The mutations promote association of endocytosed transferrin with Rab8a-positive lysosomes. Given LRRK2’s involvement in cellular responses to proinflammatory signals and its activation in microglia in postmortem PD tissue, the authors examined patient-derived and animal models.
iPSC-derived microglia from patients carrying the common G2019S LRRK2 mutation misroute transferrin to lysosomes near the nucleus under proinflammatory conditions. G2019S knock-in mice show increased iron deposition in microglia after intrastriatal inflammatory challenge compared to wild-type mice, along with striatal accumulation of ferritin. Together, these findings support a role for LRRK2 in modulating iron uptake and storage in microglia in response to inflammatory stimuli, linking a genetic cause of PD to iron dysregulation that may be therapeutically relevant.