Department of Biochemistry, La Trobe University, Vic., Australia.
Hum Mol Genet. 2013 Feb 15;22(4):717-28. doi: 10.1093/hmg/dds479. Epub 2012 Nov 19.
Fused in sarcoma (FUS) is mutated in both sporadic amyotrophic lateral sclerosis (ALS) and familial ALS patients. The mechanisms underlying neurodegeneration are not fully understood, but FUS redistributes from the nucleus to the cytoplasm in affected motor neurons, where it triggers endoplasmic reticulum (ER) stress. Ataxin-2 is a polyglutamine protein which normally contains 22 repeats, but expanded repeats (>34) are found in Spinocerebellar Ataxia type 2. Recently ataxin-2 with intermediate length repeats (27-33) was found to increase the risk of ALS. Here we show that ataxin-2 with an ALS-linked intermediate length repeat (Q31) is a potent modifier of FUS pathology in cellular disease models. Translocation of FUS to the cytoplasm and ER stress were significantly enhanced by co-expression of mutant FUS with ataxin-2 Q31. Ataxin-2 also co-localized with FUS in sporadic and FUS-linked familial ALS patient motor neurons, co-precipitated with FUS in ALS spinal cord lysates, and co-localized with FUS in the ER-Golgi compartments in neuronal cell lines. Fragmentation of the Golgi apparatus is linked to neurodegeneration in ALS and here we show that Golgi fragmentation is induced in cells expressing mutant FUS. Moreover, Golgi fragmentation was enhanced, and the early stages of apoptosis were triggered, when ataxin-2 Q31 was co-expressed with mutant FUS. These findings describe new cellular mechanisms linking ALS with ataxin-2 intermediate length polyQ expansions and provide further evidence linking disruption to ER-Golgi compartments and FUS pathology in ALS.
融合肉瘤（FUS）在散发性肌萎缩侧索硬化症（ALS）和家族性 ALS 患者中均发生突变。导致神经退行性变的机制尚未完全阐明，但 FUS 在受影响的运动神经元中从核内重新分布到细胞质，在那里它引发内质网（ER）应激。Ataxin-2 是一种多聚谷氨酰胺蛋白，正常情况下含有 22 个重复，但在脊髓小脑性共济失调 2 型中发现了扩展的重复（>34）。最近发现，具有中间长度重复（27-33）的 ataxin-2 会增加 ALS 的风险。在这里，我们表明，具有与 ALS 相关的中间长度重复（Q31）的 ataxin-2 是细胞疾病模型中 FUS 病理学的有效修饰物。通过共表达突变 FUS 和 ataxin-2 Q31，FUS 向细胞质和 ER 应激的易位显著增强。Ataxin-2 还与散发性和 FUS 相关家族性 ALS 患者运动神经元中的 FUS 共定位，在 ALS 脊髓裂解物中与 FUS 共沉淀，并在神经元细胞系的 ER-Golgi 隔室中与 FUS 共定位。高尔基器的碎片化与 ALS 中的神经退行性变有关，在这里我们表明，表达突变 FUS 的细胞中会诱导高尔基器的碎片化。此外，当共表达 ataxin-2 Q31 与突变 FUS 时，高尔基器的碎片化增强，并引发早期凋亡。这些发现描述了将 ALS 与 ataxin-2 中间长度多聚 Q 扩展联系起来的新细胞机制，并提供了进一步的证据，证明 ER-Golgi 隔室的破坏与 ALS 中的 FUS 病理学有关。
