Pathological features of Parkinson's disease include the formation of Lewy bodies containing α‐synuclein and the accumulation of iron in the substantia nigra. Previous studies have suggested that iron accumulation contributes to the Parkinson's disease pathology through reactive oxygen species production and accelerated α‐synuclein aggregation. This study examines the effects of commonly occurring H63D variant of the homeostatic iron regulatory (HFE) gene on α‐synuclein pathology in cell culture and animal models. H63D HFE expression in SH‐SY5Y cells lowered endogenous α‐synuclein levels and significantly decreased pre‐formed fibril‐induced α‐synuclein aggregation. H63D HFE cells were also protected from pre‐formed fibril‐induced apoptosis. Autophagic flux, a major pathway for α‐synuclein clearance, was increased in H63D HFE cells. Expression of REDD1 was elevated and rapamycin treatment was unable to further induce autophagy, indicating mTORC1 inhibition as the main mechanism of autophagy induction. Moreover, siRNA knockdown of REDD1 in H63D HFE cells decreased autophagic flux and increased the sensitivity to PFF‐mediated toxicity. While iron chelator (deferiprone) treatment rescued WT HFE cells from pre‐formed fibril toxicity, it exacerbated or was unable to rescue H63D HFE cells. In the in vivo pre‐formed fibril intracranial injection model, H67D Hfe (mouse homolog of the human H63D HFE variant) C57BL/6J × 129 mice showed less α‐synuclein aggregation and less decline in motor function compared to WT Hfe . Collectively, this study suggests that H63D HFE variant modifies α‐synuclein pathology through the induction of autophagy and has the potential to impact the pathogenesis and treatment response in Parkinson's disease.

中文翻译：

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稳态铁调节剂（HFE）基因的H63D变体会改变α-突触核蛋白的表达，聚集和毒性。

帕金森氏病的病理特征包括含有α-突触核蛋白的路易小体的形成和黑质中铁的积累。先前的研究表明，铁的积累通过产生活性氧和加速α-突触核蛋白的聚集而有助于帕金森氏病的病理。这项研究检查了细胞培养和动物模型中稳态铁调节（HFE）基因的常见H63D变体对α-突触核蛋白病理的影响。SH-SY5Y细胞中的H63D HFE表达降低了内源性α-突触核蛋白水平，并显着降低了预形成的原纤维诱导的α-突触核蛋白聚集。H63D HFE还保护细胞免受预先形成的原纤维诱导的细胞凋亡。自噬通量是α-突触核蛋白清除的主要途径，在H63D HFE细胞中增加了。REDD1的表达升高，雷帕霉素处理无法进一步诱导自噬，表明mTORC1抑制是自噬诱导的主要机制。此外，H63D HFE细胞中REDD1的siRNA敲低降低了自噬通量并增加了对PFF介导毒性的敏感性。尽管铁螯合剂（去铁酮）治疗使WT HFE细胞免于预先形成的原纤维毒性，但加剧或无法挽救H63D HFE细胞。在体内预先形成的原纤维颅内注射模型，H67D HFE（人H63D HFE变体的小鼠同源物）与WT Hfe相比，C57BL / 6J×129小鼠显示出更少的α-突触核蛋白聚集和更少的运动功能下降。总体而言，这项研究表明，H63D HFE变异体通过诱导自噬改变了α-突触核蛋白的病理学，并可能影响帕金森氏病的发病机理和治疗反应。