Aggregation of mutant cysteine string protein-α via Fe-S cluster binding is mitigated by iron chelators.
Aggregation of mutant cysteine string protein-α via Fe-S cluster binding is mitigated by iron chelators.
复制标题
铁螯合剂可以减轻突变型半胱氨酸串蛋白-α 通过 Fe-S 簇结合的聚集。
DOI：
10.1038/s41594-020-0375-y
复制
发表时间：
2020
影响因子：
16.8
通讯作者：
Sharma,Manu
中科院分区：
文献类型：
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作者：
Naseri,NimaN;Ergel,Burçe;Kharel,Parinati;Na,Yoonmi;Huang,Qingqiu;Huang,Rong;Dolzhanskaya,Natalia;Burré,Jacqueline;Velinov,MilenT;Sharma,Manu
半胱氨酸弦蛋白-α (CSPα)的点突变主要导致遗传性成人发病的神经元类神经脂褐质病（ANCL），这是一种快速发展且致命的神经退行性疾病，无法治疗。ANCL突变被认为可以触发CSPα聚集/寡聚，但寡聚物形成的机制尚不清楚。在这里，我们使用纯化蛋白、小鼠原代神经元和患者来源的诱导神经元来证明CSPα正常棕榈酰化的半胱氨酸链区域在ANCL突变体中失去棕榈酰化。这允许突变体CSPα通过铁硫（Fe-S）簇的异位结合进行寡聚化。突变体CSPα的寡聚化导致其定位错误，从而导致其突触snare伴随功能的丧失。然后我们发现，药理学铁螯合可以减轻突变体CSPα的寡聚化，同时部分修复下游SNARE缺陷和脂褐素积累的病理标志。因此，铁螯合剂去铁素（L1）和去铁胺（Dfx）已经被用于治疗人类铁超载，为治疗ANCL提供了一种新的方法。
Point mutations in cysteine string protein-α (CSPα) cause dominantly inherited adult-onset neuronal ceroid lipofuscinosis (ANCL), a rapidly progressing and lethal neurodegenerative disease with no treatment. ANCL mutations are proposed to trigger CSPα aggregation/oligomerization, but the mechanism of oligomer formation remains unclear. Here we use purified proteins, mouse primary neurons and patient-derived induced neurons to show that the normally palmitoylated cysteine string region of CSPα loses palmitoylation in ANCL mutants. This allows oligomerization of mutant CSPα via ectopic binding of iron–sulfur (Fe–S) clusters. The resulting oligomerization of mutant CSPα causes its mislocalization and consequent loss of its synaptic SNARE-chaperoning function. We then find that pharmacological iron chelation mitigates the oligomerization of mutant CSPα, accompanied by partial rescue of the downstream SNARE defects and the pathological hallmark of lipofuscin accumulation. Thus, the iron chelators deferiprone (L1) and deferoxamine (Dfx), which are already used to treat iron overload in humans, offer a new approach for treating ANCL.