Genetic Engineering Laboratory, College of Biological and Environmental Engineering, Xi'an University, Xi'an, Shaanxi, China.
Institute of Medical Genetics & Applied Genomics, University of Tuebingen, Tuebingen, Germany.
CNS Neurosci Ther. 2018 May;24(5):404-411. doi: 10.1111/cns.12795. Epub 2018 Jan 9.
BACKGROUND & AIMS: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal dominantly inherited neurodegenerative disorder and the most common form of SCA worldwide. It is caused by the expansion of a polyglutamine (polyQ) tract in the ataxin-3 protein. Nuclear localization of the affected protein is a key event in the pathology of SCA3 via affecting nuclear organization, transcriptional dysfunction, and seeding aggregations, finally causing neurodegeneration and cell death. So far, there is no effective therapy to prevent or slow the progression of SCA3.
In this study, we explored the effect of divalproex sodium as an HDACi in SCA3 cell models and explored how divalproex sodium interferes with pathogenetic processes causing SCA3.
We found that divalproex sodium rescues the hypoacetylation levels of histone H3 and attenuates cellular cytotoxicity induced by expanded ataxin-3 partly via preventing nuclear transport of ataxin-3 (particularly heat shock-dependent).
Our study provides novel insights into the mechanisms of action of divalproex sodium as a possible treatment for SCA3, beyond the known regulation of transcription.
脊髓小脑共济失调 3 型（SCA3），又称 Machado-Joseph 病（MJD），是一种常染色体显性遗传性神经退行性疾病，也是全球最常见的 SCA 形式。它是由 ataxin-3 蛋白中的多聚谷氨酰胺（polyQ）链的扩展引起的。受影响蛋白的核定位是 SCA3 病理学中的一个关键事件，通过影响核组织、转录功能障碍和种子聚集，最终导致神经退行性变和细胞死亡。到目前为止，还没有有效的治疗方法可以预防或减缓 SCA3 的进展。
在这项研究中，我们探讨了丙戊酸钠作为 HDACi 在 SCA3 细胞模型中的作用，并探讨了丙戊酸钠如何干扰导致 SCA3 的致病过程。
我们发现丙戊酸钠通过防止 ataxin-3 的核转运（特别是热休克依赖性），部分挽救了组蛋白 H3 的低乙酰化水平，并减轻了扩展的 ataxin-3 诱导的细胞毒性。
我们的研究为丙戊酸钠作为 SCA3 治疗药物的作用机制提供了新的见解，超出了已知的转录调节作用。
