Deficiency of PLA2G6 Induces Ferroptosis in Dopaminergic Neurons and Contributes to Parkinson's Disease Pathogenesis via Disruption of PRDX6/FTH1/GPX4 Axis.

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the progressive loss of dopaminergic neurons. Mutations in the PLA2G6 gene, which encodes calcium-independent phospholipase A2 (iPLA2β), have been associated with autosomal recessive early-onset parkinsonism, a subtype of neurodegeneration marked by brain iron accumulation. Although the pathogenic mechanisms underlying PLA2G6-related neurodegeneration remains unclear, disturbances in iron metabolism, neuroinflammation, and mitochondrial dysfunction are thought to play key roles. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently been implicated in PD. Here, we demonstrate that the iPLA2β deficiency in dopaminergic neurons induces ferroptosis, aggravating neurodegeneration and motor deficits in a mouse model of PLA2G6-associated neurodegeneration (PLAN). This ferroptotic phenotype is characterized by increased iron accumulation, elevated lipid peroxidation, and impaired antioxidant defenses, including downregulation of ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4). We further identify peroxiredoxin 6 (PRDX6) as a direct binding partner of iPLA2β and a critical regulator of ferroptosis. Loss of iPLA2β destabilizes PRDX6, promoting its degradation and thereby enhancing ferroptotic susceptibility. Notably, restoration of PRDX6 expression alleviates ferroptosis in iPLA2β-deficient cells, highlighting the protective role for the PRDX6/FTH1/GPX4 axis in maintaining redox homeostasis. Furthermore, treatment with the ferroptosis inhibitor Liproxstatin-1 (Lip-1) attenuated motor dysfunction and dopaminergic neuron loss in PLA2G6 knockout (KO) mice. Collectively, our findings uncover a novel mechanism linking iPLA2β deficiency to ferroptosis in PD and suggest ferroptosis inhibition as a promising therapeutic strategy for PD patients with PLA2G6 mutations.