α-synuclein over expression, NRF2 suppression, and enhanced ferroptosis creates a vicious cycle of neuronal loss in Parkinson's disease

Parkinsons disease (PD) is the second most common neurodegenerative disorder, affecting millions each year. Most PD cases ([~]90%) are sporadic, resulting from the age-dependent accumulation of pathogenic effects. One key pathological hallmark of PD progression is the accumulation of alpha-synuclein (-syn), which has been shown to negatively affect neuronal function and viability. Here, using 3- and 6-month-old Nrf2+/+ and Nrf2-/- mice overexpressing human -syn (PD model), we show that loss of NRF2 increases markers of ferroptosis across PD-relevant brain regions. Increased ferroptosis was associated with an age- and genotype-dependent increase in -syn pathology and behavioral deficits. Finally, we demonstrate that -syn overexpression sensitizes neuronal cells and ex vivo brain slices to ferroptosis induction, which may be due to -syn suppression of NRF2 at the protein level. Altogether, these results indicate that NRF2 is a critical anti-ferroptotic mediator of neuronal survival, and that the vicious cycle of -syn overexpression and NRF2 suppression, leading to enhanced neuronal ferroptotic cell death, could represent a targetable and currently untapped means of preventing PD onset and progression.