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

Anandhan A, Chen W, Nguyen N, Madhavan L, Dodson M, D. D. Zhang

Research output: Contribution to journalReview articlepeer-review

16 Scopus citations

Abstract

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 (α-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 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 overexpression sensitizes neuronal cells and ex vivo brain slices to ferroptosis induction, which may be due to α-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 α-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.

Original languageEnglish (US)
Pages (from-to)130-140
Number of pages11
JournalFree Radical Biology and Medicine
Volume192
DOIs
StatePublished - Nov 1 2022

Keywords

  • Nrf2
  • Parkinson's disease
  • aging
  • alpha-synuclein
  • ferroptosis

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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