Cardiovascular Department, IRCCS MultiMedica, 20138 Milan, Italy.
Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Salerno, Italy.
Int J Mol Sci. 2022 Dec 5;23(23):15313. doi: 10.3390/ijms232315313.
Huntington's disease (HD) is caused by the production of mutant Huntingtin (mHTT), characterized by long polyglutamine repeats with toxic effects. There are currently no clinically validated therapeutic agents that slow or halt HD progression, resulting in a significant clinical unmet need. The striatum-derived STHdh cell line, generated from mHTT knock-in mouse embryos (STHdh), represents a useful model to study mechanisms behind pathogenesis of HD and to investigate potential new therapeutic targets. Indeed, these cells show susceptibility to nucleolar stress, activated DNA damage response and apoptotic signals, and elevated levels of H3K9me3 that all together concur in the progressive HD pathogenesis. We have previously shown that the adeno-associated viral vector-mediated delivery of the prevents HD progression in a mouse model of HD. Here, we show that LAV-BPIFB4 stably infected in STHdh cells reduces (i) nucleolar stress and DNA damage through the improvement of DNA repair machinery, (ii) apoptosis, through the inhibition of the caspase 3 death signaling, and (iii) the levels of H3K9me3, by accelerating the histone clearance, via the ubiquitin-proteasome pathway. These findings pave the way to propose LAV-BPIFB4 as a promising target for innovative therapeutic strategies in HD.
亨廷顿病（HD）是由突变亨廷顿蛋白（mHTT）的产生引起的，其特征是具有毒性作用的长聚谷氨酰胺重复序列。目前尚无临床验证的治疗药物能够减缓或阻止 HD 的进展，因此存在巨大的临床未满足需求。源自 mHTT 敲入小鼠胚胎的纹状体来源的 STHdh 细胞系（STHdh）是研究 HD 发病机制背后的机制和研究潜在新治疗靶点的有用模型。事实上，这些细胞对核仁应激、激活的 DNA 损伤反应和凋亡信号敏感，并且 H3K9me3 水平升高，所有这些都共同导致 HD 的进行性发病。我们之前已经表明，腺相关病毒载体介导的递送可以防止 HD 模型中的 HD 进展。在这里，我们表明，LAV-BPIFB4 稳定感染 STHdh 细胞可通过以下方式减少（i）核仁应激和 DNA 损伤：改善 DNA 修复机制；（ii）通过抑制半胱天冬酶 3 死亡信号来抑制细胞凋亡；以及（iii）通过泛素-蛋白酶体途径加速组蛋白清除，从而降低 H3K9me3 水平。这些发现为将 LAV-BPIFB4 作为 HD 创新治疗策略的有前途的靶标铺平了道路。
