Ravichandran Nandita, Iyer Mahalaxmi, Uvarajan Deenathayalan, Kirola Laxmi, Kumra Sindduja Muthu, Babu Harysh Winster Suresh, HariKrishnaReddy Dibbanti, Vellingiri Balachandar, Narayanasamy Arul
Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, 641046, Tamil Nadu, India.
Department of Microbiology, Central University of Punjab, Bathinda, 151401, Punjab, India.
Metab Brain Dis. 2025 Jan 7;40(1):90. doi: 10.1007/s11011-024-01500-x.
A multifaceted and widely prevalent neurodegenerative disease, Parkinson's disease (PD) is typified by the loss of dopaminergic neurons in the midbrain. The discovery of novel treatment(s) that can reverse or halt the course of the disease progression along with identifying the most reliable biomarker(s) in PD remains the crucial concern. RhoA in its active state has been demonstrated to interact with three distinct domains located in the central coiled-coil region of ROCK. RhoA appears to activate effectors most frequently by breaking the intramolecular autoinhibitory connections, which releases functional domains from the effector protein. Additionally, RhoA is highly expressed in the nervous system and it acts as a central molecule for its several downstream effector proteins in multiple signalling pathways both in neurons and glial cells. Mitochondrial dysfunction, vesicle transport malfunction and aggregation of α-Synuclein, a presynaptic neuronal protein genetically and neuropathologically associated with PD. While the RhoA-ROCK signalling pathway appears to have a significant role in PD symptoms, suggesting it could be a promising target for therapeutic interventions. Thus, this review article addresses the potential involvement of the RhoA-ROCK signalling system in the pathophysiology of neurodegenerative illnesses, with an emphasis on its biology and function. We also provide an overview of the state of research on RhoA regulation and its downstream biological activities, focusing on the role of RhoA signalling in neurodegenerative illnesses and the potential benefits of RhoA inhibition as a treatment for neurodegeneration.
帕金森病（PD）是一种多方面且广泛流行的神经退行性疾病，其典型特征是中脑多巴胺能神经元的丧失。发现能够逆转或阻止疾病进展过程的新型治疗方法以及确定帕金森病中最可靠的生物标志物仍然是至关重要的关注点。已证明处于活性状态的RhoA与位于ROCK中央卷曲螺旋区域的三个不同结构域相互作用。RhoA似乎最常通过打破分子内自抑制连接来激活效应器，从而从效应蛋白中释放功能结构域。此外，RhoA在神经系统中高度表达，并且在神经元和神经胶质细胞的多种信号通路中作为其几种下游效应蛋白的核心分子发挥作用。线粒体功能障碍、囊泡运输故障以及α-突触核蛋白的聚集，α-突触核蛋白是一种与帕金森病在遗传和神经病理学上相关的突触前神经元蛋白。虽然RhoA-ROCK信号通路似乎在帕金森病症状中起重要作用，这表明它可能是治疗干预的一个有前景的靶点。因此，这篇综述文章探讨了RhoA-ROCK信号系统在神经退行性疾病病理生理学中的潜在参与，重点关注其生物学和功能。我们还概述了RhoA调节及其下游生物学活性的研究现状，重点关注RhoA信号在神经退行性疾病中的作用以及抑制RhoA作为神经退行性疾病治疗方法的潜在益处。
