α-Syn overexpression, NRF2 suppression, and enhanced ferroptosis create a vicious cycle of neuronal loss in Parkinson's disease

Parkinson's 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 (alpha-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 alpha-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 alpha-syn pathology and behavioral deficits. Finally, we demonstrate that alpha-syn overexpression sensitizes neuronal cells and ex vivo brain slices to ferroptosis induction, which may be due to alpha-syn decreasing NRF2 protein levels. Altogether, these results indicate that NRF2 is a critical anti-ferroptotic mediator of neuronal survival, and that the vicious cycle of alpha-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.

Automated summary

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the accumulation of alpha-synuclein and its negative effects on neuronal function and viability. This study demonstrates that loss of NRF2, a critical anti-ferroptotic mediator, increases markers of ferroptosis in PD-relevant brain regions. The increased ferroptosis is associated with age and genotype-dependent increase in alpha-syn pathology and behavioral deficits. The findings suggest targeting the vicious cycle of alpha-syn overexpression and NRF2 suppression as a potential means of preventing PD onset and progression.