Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.
5 affiliations
- 1Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA. [email protected].
- 2Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA.
- 3Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA.
- 4Center for Environmental and Human Toxicology, Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA.
- 5Center for Translational Research in Neurodegenerative Disease, Fixel Institute for Neurologic Diseases, Department of Neurology, University of Florida, Gainesville, FL, USA. [email protected].
Abstract
Background
Iron accumulation is a hallmark of sporadic and familial Parkinson's disease (PD) and correlates with clinical motor symptom severity. The biochemical mechanisms driving iron dyshomeostasis in PD brain and whether these are early or late events in the neurodegenerative process remain unknown. Nigral iron levels in LRRK2-PD patients have been reported to be even higher than in idiopathic PD, and greater in non-manifesting LRRK2 carriers than controls, suggesting that iron accumulation precedes clinical onset in LRRK2-associated PD. However, the cells affected and mechanisms governing iron dyshomeostasis in PD remain unclear.Methods
Here, we investigated multiple independent measures of iron homeostasis in human iPSCs and iPSC-derived models, including glutamatergic and dopaminergic neurons, and astrocytes, carrying pathogenic LRRK2 mutations. High-content and super-resolution microscopy of iron-specific probes and ICP-MS were used to determine iron content and distribution across different cell types and LRRK2 genotypes. Upstream effectors and downstream consequences of iron dyshomeostasis, including oxidative stress and ferroptosis-related phenotypes were also examined.Results
Pathogenic heterozygous LRRK2 mutations were associated with altered iron homeostasis across multiple human cell models. Lysosomal ferrous iron was consistently elevated across iPSC-derived glutamatergic neurons, dopaminergic neurons, and astrocytes carrying LRRK2 mutations and these phenotypes were reduced by varying degrees following treatment with the selective LRRK2 inhibitor, MLi-2. Importantly, we show that lipid peroxidation and ROS levels are elevated in isogenic LRRK2 mutant neurons, while iron chelation or MLi-2 reduced LRRK2-dependent ROS damage. In addition, CRISPR/Cas9-mediated loss of Rab8a produced overlapping iron-related phenotypes, while exogenous Rab8a expression normalized lysosomal iron levels in R1441C LRRK2 iPSCs, supporting a contributory role for Rab8a-dependent trafficking in these effects.Conclusions
Together, our findings show that pathogenic LRRK2 mutations converge on disrupted iron homeostasis across multiple human neural cell types, including dopaminergic neurons, and support a link between LRRK2 signaling, lysosomal iron dysregulation and ferroptosis-related stress.
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BibTeX
@article{mamais2026parkinsons,
title = {{Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.}},
author = {Adamantios Mamais and Richard D Batchelor and Aravindraja Chairmandurai and Thomas B Ladd and Austin J Shute and Nitya Subrahmanian and Nunziata Maio and Christopher D Vulpe and Matthew J LaVoie},
journal = {Molecular neurodegeneration},
year = {2026},
month = jul,
doi = {10.1186/s13024-026-00979-5},
url = {https://europepmc.org/article/MED/42902384},
note = {CC BY},
}
RIS
TY - JOUR
TI - Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.
AU - Adamantios Mamais
AU - Richard D Batchelor
AU - Aravindraja Chairmandurai
AU - Thomas B Ladd
AU - Austin J Shute
AU - Nitya Subrahmanian
AU - Nunziata Maio
AU - Christopher D Vulpe
AU - Matthew J LaVoie
PY - 2026
DA - 2026/07/01
JO - Molecular neurodegeneration
DO - 10.1186/s13024-026-00979-5
UR - https://europepmc.org/article/MED/42902384
AB - Background Iron accumulation is a hallmark of sporadic and familial Parkinson's disease (PD) and correlates with clinical motor symptom severity. The biochemical mechanisms driving iron dyshomeostasis in PD brain and whether these are early or late events in the neurodegenerative process remain unknown. Nigral iron levels in LRRK2-PD patients have been reported to be even higher than in idiopathic PD, and greater in non-manifesting LRRK2 carriers than controls, suggesting that iron accumulation precedes clinical onset in LRRK2-associated PD. However, the cells affected and mechanisms governing iron dyshomeostasis in PD remain unclear.Methods Here, we investigated multiple independent measures of iron homeostasis in human iPSCs and iPSC-derived models, including glutamatergic and dopaminergic neurons, and astrocytes, carrying pathogenic LRRK2 mutations. High-content and super-resolution microscopy of iron-specific probes and ICP-MS were used to determine iron content and distribution across different cell types and LRRK2 genotypes. Upstream effectors and downstream consequences of iron dyshomeostasis, including oxidative stress and ferroptosis-related phenotypes were also examined.Results Pathogenic heterozygous LRRK2 mutations were associated with altered iron homeostasis across multiple human cell models. Lysosomal ferrous iron was consistently elevated across iPSC-derived glutamatergic neurons, dopaminergic neurons, and astrocytes carrying LRRK2 mutations and these phenotypes were reduced by varying degrees following treatment with the selective LRRK2 inhibitor, MLi-2. Importantly, we show that lipid peroxidation and ROS levels are elevated in isogenic LRRK2 mutant neurons, while iron chelation or MLi-2 reduced LRRK2-dependent ROS damage. In addition, CRISPR/Cas9-mediated loss of Rab8a produced overlapping iron-related phenotypes, while exogenous Rab8a expression normalized lysosomal iron levels in R1441C LRRK2 iPSCs, supporting a contributory role for Rab8a-dependent trafficking in these effects.Conclusions Together, our findings show that pathogenic LRRK2 mutations converge on disrupted iron homeostasis across multiple human neural cell types, including dopaminergic neurons, and support a link between LRRK2 signaling, lysosomal iron dysregulation and ferroptosis-related stress.
SN - 1750-1326
ER -