Persistent remodeling and neurodegeneration in late-stage retinal degeneration

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 longterm 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 timecourse 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.

Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa

“…Double immunostaining for pS6 Ser240/244 and calbindin showed a decrease in the number of calbindin-positive tips due to retraction of horizontal terminal fibers caused by photoreceptor loss (Cuenca et al, 2014, Pfeiffer et al, 2020. Moreover, in the rd10 retina half of the remaining horizontal cell terminal tips were devoid of pS6 Ser240/244 labeling ( Fig.…”

“…Interestingly, in rd10 retinas INSR downregulation and consequent impairment of INSR signaling coincided with the presence of disconnected but otherwise apparently viable rod terminals. Alterations in retinal synaptic circuitry as part of retinal remodeling during photoreceptor degeneration have been acknowledged for more than two decades (Jones, Kondo et al, 2012, Lewis, Linberg et al, 1998, Pfeiffer et al, 2020, Strettoi, Pignatelli et al, 2003. De-afferentiation of second-order neurons has typically been described in advanced stages of degeneration as a consequence of photoreceptor loss (Jones et al, 2012, Lewis et al, 1998, Pfeiffer et al, 2020, Strettoi et al, 2003.…”

“…As part of the central nervous system (CNS), the retina shares multiple pathophysiological features with the brain . Despite their diverse etiology, retinal neurodegenerative diseases, like those affecting the brain, are characterized by synaptic failure and neuronal cell death (Pfeiffer, Marc et al, 2020). Retinitis pigmentosa (RP) comprises a group of hereditary retinal neurodegenerative conditions with a complex genetic etiology.…”

“…To date more than 60 genes and 3,000 mutations have been implicated in RP, and over 300 genes associated with inherited retinal dystrophies (https://sph.uth.edu/retnet/disease.htm) have been identified. RP is characterized by primary dysfunction and death of photoreceptor cells followed by reactive gliosis and remodeling of the retinal structure, resulting in vision loss and eventual blindness (Cuenca, Fernandez-Sanchez et al, 2014, Pfeiffer et al, 2020. RP is categorized as a rare disease (prevalence 1/3,500-4,000), but accounts for most cases of hereditary blindness.…”

A Pathoconnectome of Early Neurodegeneration

“…In addition, recent work has demonstrated that retina behaves similarly to CNS with respect to late stage disease with many of the same features observed in retina as in other neuropathies of the brain. 14 These features also make the retina an ideal candidate for mapping neuronal network disruptions that occur as a result of neurological disease by creating connectomes of pathological tissue: Pathoconnectomes. Here, we introduce the structure, features, and initial findings from Retinal Pathoconnectome 1 (RPC1) an open-access, serial-section transmission electron microscopy (ssTEM) connectome volume, generated from a rabbit model of autosomal-dominant conesparing retinitis pigmentosa (RP).…”