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.

中文翻译：

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铁螯合剂减轻了通过Fe-S簇结合引起的突变半胱氨酸串蛋白-α的聚集。

半胱氨酸串蛋白-α（CSPα）的点突变引起显性遗传的成年发作的神经元类脂脂褐变（ANCL），这是一种快速发展且致命的神经退行性疾病，无需治疗。提出了ANCL突变来触发CSPα聚集/寡聚化，但寡聚体形成的机制仍不清楚。在这里，我们使用纯化的蛋白，小鼠原代神经元和患者衍生的诱导神经元来显示CSPα的正常棕榈酰化半胱氨酸串区域在ANCL突变体中失去了棕榈酰化作用。这允许通过异位结合铁硫（Fe-S）簇来突变CSPα。突变体CSPα的低聚导致其错位，并因此丧失了其突触SNARE陪伴功能。然后，我们发现药理学上的铁螯合减轻了突变体CSPα的寡聚化，并伴随着下游SNARE缺陷的部分抢救和脂褐素积聚的病理学标志。因此，已经用于治疗人类铁超负荷的铁螯合剂去铁酮（L1）和去铁胺（Dfx）提供了一种治疗ANCL的新方法。