Tahir Waqas, Thapa Simrika, Schatzl Hermann M
Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine; Calgary Prion Research Unit; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Neural Regen Res. 2022 Aug;17(8):1659-1665. doi: 10.4103/1673-5374.332202.
Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein (PrP) into the pathologic isoform PrP. Pathologic hallmarks of prion disease are depositions of pathological prion protein PrP, neuronal loss, spongiform degeneration and astrogliosis in the brain. Prion diseases affect human and animals, there is no effective therapy, and they invariably remain fatal. For a long time, neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis, and the contribution of non-neuronal cells like microglia and astrocytes was considered less important. Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain, but the exact role of these non-neuronal cells during prion pathology is still elusive. Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions. However, astrocytes can deposit PrP aggregates and propagate prions in prion-infected brains. Additionally, sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified, differentially expressed in the brain during prion infection. Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes. Recently, we established a murine astrocyte cell line persistently infected with mouse-adapted prions, and showed how such astrocytes differentially process various prion strains. Considering the complexity of the role of astrocytes in prion pathogenesis, we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes, their differential regulation of signaling cascades, and the interaction with neurons and microglia during prion pathogenesis. This will help to establish novel in vivo models and define new therapeutic targets against prion diseases. In this review, we will discuss the complex role of astrocytes in prion disease, the existing experimental resources, the challenges to analyze the contribution of astrocytes in prion disease pathogenesis, and future strategies to improve the understanding of their role in prion disease.
朊病毒疾病是中枢神经系统的传染性蛋白质错误折叠疾病，由细胞朊蛋白（PrP）错误折叠为病理性异构体PrP所致。朊病毒疾病的病理特征是病理性朊蛋白PrP的沉积、神经元丢失、海绵状变性和大脑中的星形胶质细胞增生。朊病毒疾病影响人类和动物，目前尚无有效治疗方法，并且总是致命的。长期以来，神经元丢失被认为是朊病毒发病机制中神经退行性变的唯一原因，而小胶质细胞和星形胶质细胞等非神经元细胞的作用被认为不太重要。最近的证据表明，朊病毒发病机制中的神经退行性变是大脑中神经元和非神经元细胞之间复杂相互作用的结果，但这些非神经元细胞在朊病毒病理学中的具体作用仍不清楚。星形胶质细胞是在生理条件下调节大脑内环境稳定的非神经元细胞。然而，星形胶质细胞可在朊病毒感染的大脑中沉积PrP聚集体并传播朊病毒。此外，已鉴定出包括神经营养和神经毒性类型的反应性星形胶质细胞亚群，在朊病毒感染期间在大脑中差异表达。由于缺乏朊病毒感染星形胶质细胞的体外模型，揭示星形胶质细胞在朊病毒疾病中的具体作用受到阻碍。最近，我们建立了一种持续感染小鼠适应朊病毒的小鼠星形胶质细胞系，并展示了这种星形胶质细胞如何差异处理各种朊病毒株。考虑到星形胶质细胞在朊病毒发病机制中作用的复杂性，我们需要更多的体外和体内模型来探索反应性星形胶质细胞亚群的贡献、它们对信号级联的差异调节以及在朊病毒发病机制中与神经元和小胶质细胞的相互作用。这将有助于建立新的体内模型并确定针对朊病毒疾病的新治疗靶点。在本综述中，我们将讨论星形胶质细胞在朊病毒疾病中的复杂作用、现有的实验资源、分析星形胶质细胞在朊病毒疾病发病机制中贡献的挑战以及未来提高对其在朊病毒疾病中作用理解的策略。
