Cell study links abnormal LRRK2 activity to oxidative stress and ferroptosis

Written by Andrea Lobo | Sept. 4, 2026

• Parkinson’s-linked LRRK2 mutations were associated with abnormal iron buildup in neurons and astrocytes in laboratory cell models.
• The mutations were also linked to oxidative stress and lipid damage associated with ferroptosis, an iron-dependent form of regulated cell death.
• Experimental LRRK2 inhibition reduced excess iron and lipid peroxidation in the cell models, pointing to iron regulation as a potential therapeutic target.

Disease-causing mutations in the LRRK2 gene may disrupt iron regulation and promote cell damage, potentially contributing to the loss of dopamine-producing nerve cells in Parkinson’s disease, a study found.

The findings suggest that abnormal LRRK2 protein activity may contribute to iron accumulation inside cells and promote oxidative stress and processes linked to ferroptosis, an iron-dependent form of regulated cell death.

“What we discovered is that mutations in the LRRK2 gene directly change the way cells handle iron,” Matthew J. LaVoie, PhD, director of the University of Florida’s Center for Translational Research in Neurodegenerative Disease and one of the researchers who led the study, said in a press release.

LRRK2 mutations may link Parkinson’s to abnormal iron buildup

The study, “Parkinson’s disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes,” was published in Molecular Neurodegeneration.

Parkinson’s disease is caused by the progressive loss of dopaminergic neurons, nerve cells that produce dopamine, a signaling molecule involved in motor control. These neurons are primarily found in a brain region called the substantia nigra.

Iron accumulation is thought to contribute to neuronal damage by promoting oxidative stress, an imbalance between harmful free radicals and the body’s antioxidant defenses, and ferroptosis. Mutations in LRRK2, among the most common genetic causes of Parkinson’s, have previously been linked to higher levels of iron in the substantia nigra.

However, how LRRK2 mutations affect iron regulation in human neurons and astrocytes, nerve-supporting cells that help regulate iron availability, and whether this contributes to neuronal damage, remain poorly understood.

“For the longest time, we’ve seen a correlation in living patients between iron deposition in affected regions of the brain and Parkinson’s disease, but we couldn’t understand it,” said study author Adam Mamais, PhD, a research assistant professor of neurology.

To investigate these questions, researchers used both patient-derived and gene-edited human induced pluripotent stem cell (iPSC) models carrying disease-causing LRRK2 mutations, including G2019S, R1441C, R1441G, and Y1699C, to study their effects on iron regulation. iPSCs are made by reprogramming adult cells into a stem cell-like state, after which they can be guided to develop into different cell types.