Blocking ferroptosis shields neurons from α-synuclein toxicity in Parkinson's models

Parkinson's disease (PD) involves α-synuclein aggregation, iron accumulation in the substantia nigra pars compacta (SNc), and loss of dopaminergic neurons. Current therapies manage motor symptoms but do not halt degeneration. Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, fits many PD features, yet clinical iron chelation has produced mixed results. In a phase 2 trial, deferiprone worsened symptoms. This study examined how α-synuclein pathology relates to ferroptosis vulnerability.

The team used immunohistochemistry on midbrain sections from 10 PD patients and 11 age-matched controls. They quantified six markers (ferritin, ferroportin, NCOA4, cytochrome c, GPX4, 4HNE) in individual neurons, comparing PD neurons with and without α-synuclein inclusions to control neurons. In controls, they also compared lateral, ventral, and medial SNc subregions. They added digital spatial transcriptomics (NanoString GeoMx) of tyrosine hydroxylase-positive neurons, analyzing a curated list of 76 ferroptosis-related genes. Functional tests used differentiated human LUHMES dopaminergic neurons and mouse primary cortical neurons exposed to α-synuclein fibrils (61-140) and the GPX4 inhibitor RSL3, with or without ferrostatin-1 (Fer-1) or deferoxamine (DFO). Cell death was measured by propidium iodide uptake. An α-synuclein-expressing C. elegans model was used to assess iron levels and inclusions.

In post-mortem tissue, ferritin and ferroportin were significantly lower in neurons with α-synuclein inclusions than in control neurons, suggesting impaired iron storage and export. Ferroportin was also reduced in inclusion-negative PD neurons, though less than in inclusion-positive ones. 4HNE, a lipid peroxidation product, was higher in inclusion-negative PD neurons than in controls. In controls, several markers differed across SNc subregions, with the medial region showing the highest levels of several markers, suggesting regional differences in ferroptosis vulnerability. Spatial transcriptomics identified ferroptosis-related differentially expressed genes that collectively pointed to greater vulnerability in PD.

In cell models, low concentrations of α-synuclein or RSL3 alone did not kill neurons, but together they increased death in both dopaminergic and cortical neurons. Fer-1 mitigated this death, whereas DFO did not. In C. elegans, α-synuclein expression raised iron levels, ferritin knockdown worsened this, and DFO lowered iron and reduced α-synuclein inclusions.

The findings support ferroptosis as a contributor to α-synuclein-related neuronal death and suggest that blocking lipid peroxidation may be more protective than chelating iron in some contexts. Caveats include the small post-mortem cohort, end-stage disease, which limited subregion comparisons in PD, and the cell- and model-dependent responses. Effective therapy may need to target multiple parts of the pathway and consider timing.