Pyridoxal phosphate inhibits alpha-synuclein-induced ferroptosis by activating GOT1 to enhance the methionine salvage pathway in Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the overpression of α-synuclein (α-syn) and the degeneration of dopaminergic neurons. Ferroptosis, a form of cell death driven by aberrant iron metabolism and lipid peroxidation, has been reported to play a crucial role in the pathogenesis of dopaminergic neurons death while the precise mechanisms remain elusive. In this study, we identified a cytosolic enzyme glutamic-oxalacetic transaminase (GOT)-1 as a negative regulator of ferroptosis through analyses of public databases. Inhibition of GOT1 exaggerated the ferroptosis of dopaminergic neurons death in both in vitro and in vivo PD models. Furthermore, database analysis showed that GOT1 modulate ferroptosis via its intrinsic enzymatic role: depletion of GOT1 substantially blocked the salvage synthesis of methionine and its downstream product glutathione (GSH), which led to oxidative stress and neuronal ferroptosis. Importantly, we found that pyridoxal phosphate (Vitamin B6), a well-used drug in clinical practice, could activate GOT1 thereby enhance the synthesis of methionine and alleviate neuronal ferroptosis. In conclusion, we identified GOT1 as a critical protector of dopaminergic neurons via inhibiting ferroptosis. Activation of GOT1 by pyridoxal phosphate could therefore be a promising therapeutic strategy for patient with PD. Clinical studies are warranted to validate the new translational value of this common-prescribed drug.