Department of Neurology, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan.
Division of Pure and Applied Science, Faculty of Science and Technology, Gunma University, Maebashi, Gunma, 371-8510, Japan.
Neurosci Res. 2021 Oct;171:92-102. doi: 10.1016/j.neures.2021.03.001. Epub 2021 Mar 8.
Spinocerebellar ataxia type 36 (SCA36) is a noncoding repeat expansion disorder caused by an expanded GGCCTG hexanucleotide repeat (HNR) in the first intron of the nucleolar protein 56 (NOP56) gene. Another disease-causing HNR expansion derived from C9orf72-linked GGGGCC repeats that form G-quadruplexes (GQs) affects genetic stability, RNA splicing, and mRNA localization within neurites. The porphyrin derivative TMPyP4 was shown to ameliorate RNA toxicity caused by GGGGCC HNR expansion by binding and distorting RNA GQ structures. SCA36 GGCCTG HNRs can potentially form RNA GQs; therefore, we investigated whether several porphyrin derivatives could reduce RNA toxicity in SCA36 cell models. Among these, sodium copper chlorophyllin and hemin chloride, which have already been used in clinical practice, reduced SCA36 GGCCTG expansion-mediated cytotoxicity and improved cell viability. These data suggest that porphyrins are potential therapeutic candidates against SCA36 pathogenesis.
脊髓小脑性共济失调 36 型（SCA36）是一种非编码重复扩展障碍，由核仁蛋白 56（NOP56）基因第一内含子中 GGCCTG 六核苷酸重复（HNR）扩展引起。另一种致病的 HNR 扩展来源于 C9orf72 相关的 GGGGCC 重复，形成 G-四链体（GQs），影响遗传稳定性、RNA 剪接和神经突内的 mRNA 定位。卟啉衍生物 TMPyP4 通过结合和扭曲 RNA GQ 结构，减轻由 GGGGCC HNR 扩展引起的 RNA 毒性。SCA36 GGCCTG HNR 可能形成 RNA GQs；因此，我们研究了几种卟啉衍生物是否可以降低 SCA36 细胞模型中的 RNA 毒性。其中，已经在临床实践中使用的铜叶绿素钠和氯化血红素降低了 SCA36 GGCCTG 扩展介导的细胞毒性并提高了细胞活力。这些数据表明卟啉类化合物是治疗 SCA36 发病机制的潜在治疗候选物。
