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

Abstract

Parkinson's disease 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 (α-syn), which has been shown to negatively affect neuronal function and viability. Here, using 3- and 6-month-old Nrf2+/+ and Nrf2-/- mice over expressing human α-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 α-syn pathology and behavioral deficits. Finally, we demonstrate that α-syn over expression sensitizes neuronal cells and ex vivo brain slices to ferroptosis induction, which may be due to α-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 α-syn over expression and NRF2 suppression, leading to enhanced neuronal ferroptotic cell death, could represent a targetable and currently untapped means of preventing PD onset and progression.

Mapping the Research of Ferroptosis in Parkinson’s Disease from 2013 to 2023: A Scientometric Review

“… 37 , 102 Furthermore, Nrf2 deficiency leads to the up-regulation of iron death markers in PD-associated brain regions, and a vicious cycle of α-syn overexpression and NRF2 inhibition results in increased ferroptosis sensitivity of neuronal cells. 103 Coenzyme Q10 (CoQ10) and its reduced state (CoQ10-H2) are potent mitochondrial and lipid antioxidants and are considered to be the second endogenous mechanism for inhibiting ferroptosis, functioning independently of GPX4. 12 , 104 Additionally, reduced CoQ10 has been observed in PD patients and animal models, and CoQ10 supplementation has been found to attenuate PD-associated degenerative changes.…”

Identifying the potential genes in alpha synuclein driving ferroptosis of Parkinson’s disease

“…Meanwhile, the NRF2 loss may enhances the α-Syn phosphorylation, which causes oligomerization and eventual convert the α-Syn into insoluble aggregates 22 . The discovery that there is a vicious cycle of α-syn overexpression, NRF2 suppression, and enhanced ferroptotic neuronal death that could be a key driver of parkinsonian phenotypes 23 . This may explain why the α-syn can accentuate ferroptosis of PD pathology via suppression of NRF2 and if there is a physical interaction between NRF2 and α-syn will be interesting to pursue.…”

The Absence of Gastrointestinal Redox Dyshomeostasis in the Brain-First Rat Model of Parkinson’s Disease Induced by Bilateral Intrastriatal 6-Hydroxydopamine

“…Although there are differences between unilateral and bilateral 6-OHDA models [ 70 ], the absence of gastrointestinal redox dyshomeostasis in the bilateral model provides rational evidence to assume the effects would also be absent if the rats were injected unilaterally. Lastly, none of the redox biomarkers we evaluated here supported the hypothesis of gastrointestinal redox dyshomeostasis; however, the area of aging-related redox biomarkers is developing rapidly, and it is possible that the analysis of some other (more sensitive) biomarkers or signaling molecules (e.g., redox-sensitive modulatory proteins) [ 85 – 87 ] may have provided a different insight.…”