Seth Pankaj
Department of Cellular and Molecular Neuroscience, National Brain Research Centre, Gurgaon, India.
Current Address-Synaptic and Developmental Plasticity Group, Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States.
Front Cell Dev Biol. 2022 Jul 4;10:903031. doi: 10.3389/fcell.2022.903031. eCollection 2022.
Mortalin is a chaperone protein that regulates physiological functions of cells. Its multifactorial role allows cells to survive pathological conditions. Pharmacological, chemical, and siRNA-mediated downregulation of mortalin increases oxidative stress, mitochondrial dysfunction leading to unregulated inflammation. In addition to its well-characterized function in controlling oxidative stress, mitochondrial health, and maintaining physiological balance, recent evidence from human brain autopsies and cell culture-based studies suggests a critical role of mortalin in attenuating the damage seen in several neurodegenerative diseases. Overexpression of mortalin provides an important line of defense against accumulated proteins, inflammation, and neuronal loss, a key characteristic feature observed in neurodegeneration. Neurodegenerative diseases are a group of progressive disorders, sharing pathological features in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and HIV-associated neurocognitive disorder. Aggregation of insoluble amyloid beta-proteins and neurofibrillary tangles in Alzheimer's disease are among the leading cause of neuropathology in the brain. Parkinson's disease is characterized by the degeneration of dopamine neurons in substantia nigra pars compacta. A substantial synaptic loss leading to cognitive decline is the hallmark of HIV-associated neurocognitive disorder (HAND). Brain autopsies and cell culture studies showed reduced expression of mortalin in Alzheimer's, Parkinson's, and HAND cases and deciphered the important role of mortalin in brain cells. Here, we discuss mortalin and its regulation and describe how neurotoxic conditions alter the expression of mortalin and modulate its functions. In addition, we also review the neuroprotective role of mortalin under neuropathological conditions. This knowledge showcases the importance of mortalin in diverse brain functions and offers new opportunities for the development of therapeutic targets that can modulate the expression of mortalin using chemical compounds.
mortalin是一种伴侣蛋白，可调节细胞的生理功能。其多方面的作用使细胞能够在病理条件下存活。mortalin的药理学、化学和小干扰RNA介导的下调会增加氧化应激、线粒体功能障碍，从而导致炎症失控。除了在控制氧化应激、线粒体健康和维持生理平衡方面具有明确的功能外，最近来自人脑尸检和细胞培养研究的证据表明，mortalin在减轻几种神经退行性疾病中的损伤方面起着关键作用。mortalin的过表达为抵御积累的蛋白质、炎症和神经元丢失提供了重要的防线，而神经元丢失是神经退行性变中观察到的一个关键特征。神经退行性疾病是一组进行性疾病，在阿尔茨海默病、帕金森病、多发性硬化症和HIV相关神经认知障碍中具有共同的病理特征。阿尔茨海默病中不溶性淀粉样β蛋白的聚集和神经原纤维缠结是大脑神经病理学的主要原因之一。帕金森病的特征是黑质致密部多巴胺神经元的退化。导致认知能力下降的大量突触丧失是HIV相关神经认知障碍（HAND）的标志。脑尸检和细胞培养研究表明，在阿尔茨海默病、帕金森病和HAND病例中，mortalin的表达降低，并阐明了mortalin在脑细胞中的重要作用。在此，我们讨论mortalin及其调节，并描述神经毒性条件如何改变mortalin的表达并调节其功能。此外，我们还综述了mortalin在神经病理条件下的神经保护作用。这些知识展示了mortalin在多种脑功能中的重要性，并为开发能够使用化学化合物调节mortalin表达的治疗靶点提供了新的机会。
