Alpha synuclein aggregation drives ferroptosis: an interplay of iron, calcium and lipid peroxidation

Abstract

Protein aggregation and abnormal lipid homeostasis are both implicated in neurodegeneration through unknown mechanisms. Here we demonstrate that aggregate-membrane interaction is critical to induce a form of cell death called ferroptosis. Importantly, the aggregate-membrane interaction that drives ferroptosis depends both on the conformational structure of the aggregate, as well as the oxidation state of the lipid membrane. We generated human stem cell-derived models of synucleinopathy, characterized by the intracellular formation of α-synuclein aggregates that bind to membranes. In human iPSC-derived neurons with SNCA triplication, physiological concentrations of glutamate and dopamine induce abnormal calcium signaling owing to the incorporation of excess α-synuclein oligomers into membranes, leading to altered membrane conductance and abnormal calcium influx. α-synuclein oligomers further induce lipid peroxidation. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling. Inhibition of lipid peroxidation, and reduction of iron-dependent accumulation of free radicals, further prevents oligomer-induced toxicity in human neurons. In summary, we report that peroxidation of polyunsaturated fatty acids underlies the incorporation of β-sheet-rich aggregates into the membranes, and that additionally induces neuronal death. This suggests a role for ferroptosis in Parkinson’s disease, and highlights a new mechanism by which lipid peroxidation causes cell death.

Highly enriched hiPSC-derived midbrain dopaminergic neurons robustly models Parkinson’s disease

“…During disease, alpha-synuclein aggregates within neurons. To test whether the SNCA mDA neurons exhibit aggregate formation, we utilised a conformation specific antibody that recognises all types of aggregated forms of alpha-synuclein (Angelova et al, 2020). At 6 weeks post differentiation, we observed the presence of aggregated alpha-synuclein in both the A53T and the SNCA x3 line which were significantly increased compared to control (Fig.…”

The Role of α-Synuclein Oligomers in Parkinson’s Disease

“…α-syn oligomers can induce the production of reactive oxygen species (ROS) dependent on free metal ions, resulting in a decrease in endogenous glutathione and neuronal death [ 56 ]. β-sheet-rich α-syn oligomers interact with lipid membrane, bringing about abnormal calcium influx and lipid peroxidation in an iron-dependent manner [ 57 ]. The process of cell death caused by α-syn-induced lipid peroxidation is called ferroptosis.…”

Oxidative Stress and Neuroinflammation Potentiate Each Other to Promote Progression of Dopamine Neurodegeneration

“…Targeted inhibition of lipid peroxidation prevented polymerization membrane interaction, abolished abnormal calcium flux, and restored physiological calcium signal. The new mechanism of cell death caused by lipid peroxidation was emphasized [16]. The correlation between oxidative stress and PD is also reflected in the changes of familial risk factors for PD, such α-syn, PINK1 (pten-induced kinase 1), Parkin (E3 ubiquitin ligase PARK2), DJ-1 (PARK7), and LRRK2 (leucine-rich repeat kinase 2).…”

“…The aggregation-membrane interaction is the key to induce ferroptosis, which depends not only on the conformation structure of the aggregates but also on the oxidation state of the lipid membrane. Inhibition of lipid peroxidation, reduction of iron-dependent free radical accumulation, and further prevention of neuronal oligomer-induced toxicity emphasize the role of increased ferritin in PD [16]. Studies have shown that ferroptosis induced by ferric ammonium citrate (FAC) may lead to apoptosis of MES 23.5 cells, and in the pathological process of PD mice, ferritin increased earlier than apoptosis [28].…”