Persistent remodeling and neurodegeneration in late-stage retinal degeneration. (January 2020)

• Record Type: Journal Article
• Authors: Pfeiffer, Rebecca L.; Marc, Robert E.; Jones, Bryan William
• Is Part Of: Progress in retinal and eye research. Volume 74(2020:Jan.)
• Publication Date: 2020-01
• Subjects: Retinal remodeling -- Neurodegeneration -- Ultrastructure -- Alpha-synuclein -- Proteinopathy -- Transcellular debris removal; Retina -- Periodicals; Retina -- Research -- Methodology -- Periodicals; Eye -- Diseases -- Periodicals; Eye -- Periodicals; Eye Diseases -- Periodicals; Retina -- Periodicals; Rétine -- Périodiques; Rétine -- Recherche -- Méthodologie -- Périodiques; 617.7005
• DOI: 10.1016/j.preteyeres.2019.07.004
• Languages: English
• ISSNs: 1350-9462

Abstract

Abstract: 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. Highlights: The final state of retinal remodeling is neurodegeneration. Neurodegeneration in retinal remodeling demonstrates alpha-synuclein aggregates. Proteinopathy features makes the retina an ideal model for CNS neurodegeneration. Therapeutic interventions will be identified and refined based on remodeling.