Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Department of Neurology, University of Arizona, Tucson, AZ, USA.
Free Radic Biol Med. 2022 Nov 1;192:130-140. doi: 10.1016/j.freeradbiomed.2022.09.015. Epub 2022 Sep 21.
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.
帕金森病（PD）是第二常见的神经退行性疾病，每年影响数百万人。大多数 PD 病例（~90%）为散发性，是由于致病性影响随年龄的积累而导致的。PD 进展的一个关键病理标志是α-突触核蛋白（α-syn）的积累，已证明其会对神经元功能和活力产生负面影响。在这里，我们使用 Nrf2 敲除和过表达人源α-syn（PD 模型）的 3 个月和 6 个月大的 Nrf2 和 Nrf2 小鼠，表明 NRF2 的缺失会增加与 PD 相关的大脑区域中发生铁死亡的标志物。铁死亡的增加与α-syn 病理和行为缺陷的年龄和基因型依赖性增加有关。最后，我们证明α-syn 的过表达使神经元细胞和离体脑片对铁死亡诱导敏感，这可能是由于α-syn 降低了 NRF2 蛋白水平。总之，这些结果表明 NRF2 是神经元存活的关键抗铁死亡介质，而α-syn 的过表达和 NRF2 抑制的恶性循环导致增强的神经元铁死亡细胞死亡，可能是一个可靶向的、目前尚未开发的预防 PD 发病和进展的手段。
