The FMRpolyGlycine Protein Mediates Aggregate Formation and Toxicity Independent of the CGG mRNA Hairpin in a Cellular Model for FXTAS
The FMRpolyGlycine Protein Mediates Aggregate Formation and Toxicity Independent of the CGG mRNA Hairpin in a Cellular Model for FXTAS
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DOI：
10.3389/fgene.2019.00249
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发表时间：
2019-03-28
影响因子：
3.7
通讯作者：
Johansen, Terje
中科院分区：
文献类型：
--
作者：
Hoem, Gry;Larsen, Kenneth Bowitz;Johansen, Terje
脆性 X 相关震颤/共济失调综合征 (FXTAS) 是一种神经退行性疾病，由 X 染色体上 FMR1 基因 5' UTR 的 CGG 重复扩增引起。推测扩展的 FMR1 mRNA 水平升高和 CGG 重复区域聚甘氨酸蛋白 (FMRpolyG) 的异常表达会触发 FXTAS 的发病机制。虽然 FMRpolyG 表达增加会在 FXTAS 模型中导致更高的毒性，但仅在存在含有 CGG 的 mRNA 的情况下研究了该蛋白的致病作用。在这里，我们提出了一个模型，可以测量 FMRpolyG 表达的效果，而无需共表达相应的 CGG mRNA 发夹。这允许直接比较FMRpolyG蛋白本身的效果与FMRpolyG蛋白与CGG mRNA发夹一起的效果。我们的结果表明，在没有任何 CGG mRNA 的情况下，FMRpolyG 的表达足以导致细胞活力降低、核纤层蛋白环破坏和聚集体形成。此外，我们发现 FMRpolyG 是一种长寿命蛋白质，主要由泛素蛋白酶体系统降解。总之，我们的数据表明 FMRpolyG 蛋白本身的积累可能在 FXTAS 的发展中发挥重要作用。
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG-repeat expansion in the 5' UTR of the FMR1 gene on the X-chromosome. Both elevated levels of the expanded FMR1 mRNA and aberrant expression of a polyglycine protein (FMRpolyG) from the CGG-repeat region are hypothesized to trigger the pathogenesis of FXTAS. While increased expression of FMRpolyG leads to higher toxicity in FXTAS models, the pathogenic effect of this protein has only been studied in the presence of CGG-containing mRNA. Here we present a model that allows measurement of the effect of FMRpolyG-expression without co-expression of the corresponding CGG mRNA hairpin. This allows direct comparison of the effect of the FMRpolyG protein per se, vs. that of the FMRpolyG protein together with the CGG mRNA hairpin. Our results show that expression of the FMRpolyG, in the absence of any CGG mRNA, is sufficient to cause reduced cell viability, lamin ring disruption and aggregate formation. Furthermore, we found FMRpolyG to be a long-lived protein degraded primarily by the ubiquitin-proteasome-system. Together, our data indicate that accumulation of FMRpolyG protein per se may play a major role in the development of FXTAS.