Shandilya Chesta, Mani Shalini
Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Sector 62, Noida, A-10, 201301, UP, India.
Mol Biol Rep. 2025 Aug 26;52(1):846. doi: 10.1007/s11033-025-10947-9.
Mitochondria serve as an important cellular organelle for maintaining neurotransmission and synaptic plasticity in neuronal cells by playing a key role in ATP generation, maintaining calcium homeostasis, and regulating the levels of reactive oxygen species (ROS), etc. The regulation of the dynamic nature of mitochondria, including their fission, fusion, and removal of damaged mitochondria by mitophagy, is also very important for neuronal health. Abnormalities in mitochondrial processes, including but not limited to fission, fusion, and mitophagy, are known to be associated with numerous neurodegenerative diseases (NDDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). In the recent past, the Rho kinase (ROCK) isoforms, particularly ROCK1 and ROCK2, have gained a lot of attention in NDDs, mainly for their role in regulating the dynamics of the mitochondria, mitophagy, and other cell signalling pathways. By adding phosphate groups to Drp1, ROCK1 is crucial in supporting excessive mitochondrial fission, causing the death of neuronal cells. On the other hand, ROCK2 inhibits Parkin-dependent mitophagy by inhibiting the PTEN protein, the activator of Parkin-dependent mitophagy. This impaired mitochondrial quality control via reduced mitophagic flux leads to oxidative stress and neuronal degeneration, the central pathological feature of NDDs. The inhibition of ROCK isoforms has shown great promise in neuroprotective effects, controlling the dynamics of mitochondria in neuronal cells, lowering inflammation, and improving motor and cognitive functions in preclinical models of different NDDs, indicating ROCK isoforms as an attractive therapeutic target in different NDDs. This review aims to highlight the therapeutic significance of targeting ROCK isoforms in different NDDs.
线粒体是一种重要的细胞器，通过在三磷酸腺苷（ATP）生成、维持钙稳态以及调节活性氧（ROS）水平等方面发挥关键作用，来维持神经元细胞中的神经传递和突触可塑性。线粒体动态特性的调节，包括其裂变、融合以及通过线粒体自噬清除受损线粒体，对神经元健康也非常重要。已知线粒体过程的异常，包括但不限于裂变、融合和线粒体自噬，与许多神经退行性疾病（NDDs）相关，如帕金森病（PD）、阿尔茨海默病（AD）、肌萎缩侧索硬化症（ALS）和亨廷顿舞蹈病（HD）。最近，Rho激酶（ROCK）亚型，特别是ROCK1和ROCK2，在NDDs中受到了广泛关注，主要是因为它们在调节线粒体动态、线粒体自噬和其他细胞信号通路中的作用。通过向动力相关蛋白1（Drp1）添加磷酸基团，ROCK1在支持过度的线粒体裂变从而导致神经元细胞死亡方面起着关键作用。另一方面，ROCK2通过抑制PTEN蛋白（Parkin依赖性线粒体自噬的激活剂）来抑制Parkin依赖性线粒体自噬。这种通过降低线粒体自噬通量而受损的线粒体质量控制会导致氧化应激和神经元变性，这是NDDs的核心病理特征。在不同NDDs的临床前模型中，抑制ROCK亚型在神经保护作用、控制神经元细胞中线粒体的动态、减轻炎症以及改善运动和认知功能方面显示出巨大的前景，这表明ROCK亚型是不同NDDs中一个有吸引力的治疗靶点。本综述旨在强调在不同NDDs中靶向ROCK亚型的治疗意义。
