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Abstract：
Huntington\'s disease (HD) is a dominantly inherited neurodegenerative disorder featured by abnormal movements, arising from the extensive neuronal loss and glial dysfunction in the striatum. Although the causes and pathogenetic mechanisms of HD are well established, the development of disease-modifying pharmacological therapies for HD remains a formidable challenge. Laduviglusib has demonstrated neuroprotective effects through the enhancement of mitochondrial function in the striatum of HD animal models. Ferroptosis is a nonapoptotic form of cell death that occurs as a consequence of lethal iron-dependent lipid peroxidation and mitochondrial dysfunction. However, the ferroptosis-related mechanisms underlying the neuroprotective effects of laduviglusib in the striatum of HD patients remain largely uncharted. In this study, we leveraged single-nucleus RNA sequencing data obtained from the striatum of HD patients in stages 2-4 to identify differentially expressed genes within distinct cell-type. We subsequently integrated these differentially expressed genes of HD, laduviglusib target genes and ferroptosis-related genes to predict the ferroptosis-related mechanisms underpinning the neuroprotective effects of laduviglusib in HD patients. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses unveiled that the effects of laduviglusib on direct pathway striatal projection neurons (dSPNs) is mainly associated with Th17 cell differentiation pathways. Conversely, its impact on indirect pathway striatal projection neurons (iSPNs) extends to the Neurotrophin signaling pathway, FoxO signaling pathway, and reactive oxygen species pathway. In microglia, laduviglusib appears to contribute to HD pathology via mechanisms related to Th17 cell differentiation and the FoxO signaling pathway. Further, molecular docking results indicated favorable binding of laduviglusib with PARP1 (associated with dSPNs and iSPNs), SCD (associated with astrocytes), ALOX5 (associated with microglia), and HIF1A (associated with dSPNs, iSPNs, and microglia). In addition, the KEGG results suggest that laduviglusib may enhance mitochondrial function and protect against neuronal loss by targeting ferroptosis-related signaling pathways, particularly mediated by ALOX5 in microglia. These findings provide valuable insights into the potential mechanisms through which laduviglusib exerts its effects on distinct cell-types within the HD striatum.
摘要：
亨廷顿病（HD）是一种以异常运动为特征的显性遗传性神经退行性疾病，由纹状体中广泛的神经元丢失和神经胶质功能障碍引起。尽管HD的病因和发病机制已经很好地确定，改善疾病的药物治疗HD仍然是一个巨大的挑战.Laduviglusib已通过增强HD动物模型纹状体中的线粒体功能而证明了神经保护作用。铁凋亡是一种非凋亡形式的细胞死亡，是致命的铁依赖性脂质过氧化和线粒体功能障碍的结果。然而,在HD患者的纹状体中,拉杜维格鲁西布发挥神经保护作用的相关机制在很大程度上仍然未知.在这项研究中,我们利用从2-4期HD患者纹状体获得的单核RNA测序数据来鉴定不同细胞类型内的差异表达基因.我们随后整合了这些HD的差异表达基因，laduviglusib靶基因和铁凋亡相关基因预测铁凋亡相关机制支持laduviglusib在HD患者中的神经保护作用。京都基因和基因组百科全书（KEGG）和基因本体论（GO）分析揭示了laduguglusib对直接途径纹状体投射神经元（dSPN）的影响主要与Th17细胞分化途径有关。相反，它对间接途径纹状体投射神经元（iSPN）的影响延伸到神经营养蛋白信号通路，FoxO信号通路,和活性氧途径。在小胶质细胞中，laduviglusib似乎通过与Th17细胞分化和FoxO信号通路相关的机制促进HD病理。Further,分子对接结果表明拉杜维格鲁与PARP1(与dSPNs和iSPNs相关)的良好结合，SCD（与星形胶质细胞相关），ALOX5（与小胶质细胞相关），和HIF1A(与dSPN相关，iSPNs,和小胶质细胞）。此外,KEGG结果表明，拉杜维格鲁单抗可能通过靶向铁凋亡相关的信号通路来增强线粒体功能并防止神经元丢失，特别是由ALOX5介导的小胶质细胞。这些发现为laduviglusib对HD纹状体内不同细胞类型发挥作用的潜在机制提供了有价值的见解。
