Department of Neurosurgery, College of Medicine, The Pennsylvania State University, 700 HMC Crescent Road, Hershey, PA 17033, USA.
Int J Mol Sci. 2024 Mar 15;25(6):3334. doi: 10.3390/ijms25063334.
Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze reactive oxygen species production. However, whether HFE variants exacerbate or protect against neurodegeneration has been heavily debated. Some claim that mutated HFE exacerbates oxidative stress and neuroinflammation, thus predisposing carriers to neurodegeneration-linked pathologies. However, H63D HFE has also been shown to slow the progression of multiple neurodegenerative diseases and to protect against environmental toxins that cause neurodegeneration. These conflicting results showcase the need to further understand the contribution of HFE variants to neurodegenerative disease heterogeneity. Data from mouse models consistently demonstrate robust neuroprotection against toxins known to increase the risk of neurodegenerative disease. This may represent an adaptive, or hormetic, response to increased iron, which leaves cells better protected against future stressors. This review describes the current research regarding the contribution of HFE variants to neurodegenerative disease prognosis in the context of a hormetic model. To our knowledge, this is the first time that a hormetic model for neurodegenerative disease has been presented.
常见的铁调节蛋白 HFE 变体导致铁水平系统升高，但铁在大脑中的作用尚未完全阐明。人们普遍认为，铁失调是神经退行性疾病的一个关键因素，因为铁能够催化活性氧物质的产生。然而，HFE 变体是否会加剧或预防神经退行性变一直存在很大争议。一些人声称，突变的 HFE 会加剧氧化应激和神经炎症，从而使携带者易患与神经退行性变相关的病变。然而，H63D HFE 也被证明可以减缓多种神经退行性疾病的进展，并预防导致神经退行性变的环境毒素。这些相互矛盾的结果表明，需要进一步了解 HFE 变体对神经退行性疾病异质性的贡献。来自小鼠模型的数据一致表明，对已知增加神经退行性疾病风险的毒素具有强大的神经保护作用。这可能代表了对铁增加的适应性或应激反应，使细胞对未来的应激源有更好的保护。本综述描述了当前关于 HFE 变体在神经退行性疾病预后中的作用的研究，其背景是应激模型。据我们所知，这是首次提出神经退行性疾病的应激模型。
