Dept of Ophthalmology, Moran Eye Center, University of Utah, Salt Lake City, UT, USA; Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT, USA.
Dept of Ophthalmology, Moran Eye Center, University of Utah, Salt Lake City, UT, USA; Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT, USA.
Prog Retin Eye Res. 2020 Jan;74:100771. doi: 10.1016/j.preteyeres.2019.07.004. Epub 2019 Jul 26.
Retinal remodeling is a progressive series of negative plasticity revisions that arise from retinal degeneration, and are seen in retinitis pigmentosa, age-related macular degeneration and other forms of retinal disease. These processes occur regardless of the precipitating event leading to degeneration. Retinal remodeling then culminates in a late-stage neurodegeneration that is indistinguishable from progressive central nervous system (CNS) proteinopathies. Following long-term deafferentation from photoreceptor cell death in humans, and long-lived animal models of retinal degeneration, most retinal neurons reprogram, then die. Glial cells reprogram into multiple anomalous metabolic phenotypes. At the same time, survivor neurons display degenerative inclusions that appear identical to progressive CNS neurodegenerative disease, and contain aberrant α-synuclein (α-syn) and phosphorylated α-syn. In addition, ultrastructural analysis indicates a novel potential mechanism for misfolded protein transfer that may explain how proteinopathies spread. While neurodegeneration poses a barrier to prospective retinal interventions that target primary photoreceptor loss, understanding the progression and time-course of retinal remodeling will be essential for the establishment of windows of therapeutic intervention and appropriate tuning and design of interventions. Finally, the development of protein aggregates and widespread neurodegeneration in numerous retinal degenerative diseases positions the retina as a ideal platform for the study of proteinopathies, and mechanisms of neurodegeneration that drive devastating CNS diseases.
视网膜重塑是一种由视网膜变性引起的渐进性负可塑性改变，见于色素性视网膜炎、年龄相关性黄斑变性和其他形式的视网膜疾病。这些过程发生在导致变性的诱发事件发生之前。然后，视网膜重塑最终导致晚期神经退行性变，与进行性中枢神经系统（CNS）蛋白病无法区分。在人类感光细胞死亡和长期存活的视网膜变性动物模型长期去传入后，大多数视网膜神经元重新编程，然后死亡。神经胶质细胞重新编程为多种异常代谢表型。同时，存活神经元显示出退行性包含物，与进行性中枢神经系统神经退行性疾病相同，包含异常的α-突触核蛋白（α-syn）和磷酸化的α-syn。此外，超微结构分析表明了一种错误折叠蛋白转移的新的潜在机制，这可能解释了蛋白病是如何传播的。虽然神经退行性变对针对原发性光感受器丧失的视网膜介入治疗构成了障碍，但了解视网膜重塑的进展和时间进程对于确定治疗介入的窗口期以及介入的适当调整和设计至关重要。最后，在许多视网膜变性疾病中，蛋白质聚集体的发展和广泛的神经退行性变将视网膜定位为研究蛋白质病和驱动毁灭性中枢神经系统疾病的神经退行性变机制的理想平台。
