脑铁蓄积性神经变性中转铁蛋白受体棕榈酰化和再循环受损。
Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation.
机构信息
UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Laboratory of Excellence GR-Ex, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
出版信息
Am J Hum Genet. 2018 Feb 1;102(2):266-277. doi: 10.1016/j.ajhg.2018.01.003.
Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA.
神经退行性伴脑铁沉积症（NBIA）是一种遗传异质性疾病，其特征是进行性肌张力障碍伴基底节铁沉积。NBIA 相关突变如何引发铁过载仍知之甚少。在研究携带 CRAT 和 REPS1 中已知和未报道的双等位基因突变的成纤维细胞系后，我们将铁过载归因于转铁蛋白受体（TfR1）的异常循环和 NBIA 中 TfR1 的棕榈酰化减少。此外，我们将棕榈酰化描述为 TfR1 调节的一个迄今为止未被报道的翻译后水平。一种广泛使用的抗疟药物青蒿琥酯挽救了 NBIA 患者培养的成纤维细胞中异常的 TfR1 棕榈酰化。这些观察结果表明，针对 NBIA 中受损的 TfR1 循环和棕榈酰化的治疗策略是可行的。
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