Persistent Remodeling and Neurodegeneration in Late-Stage Retinal Degeneration
Creators: name: Pfeiffer, Rebecca Lynne
Publisher: name: University of Utah
Year: 2019
Subjects: subject: Neurosciences
subject: FOS: Clinical medicine
subject: Ophthalmology

description: Human retinitis pigmentosa (RP) typically involves decades of progressive vision loss before some patients become blind, and prospective therapies target patients who have been blind for substantial time, even decades. Evaluations of molecular and cellular therapies have primarily employed short-lived mouse models lacking the scope of remodeling common in human RP. The Rho Tg P347L transgenic rabbit offers a unique opportunity to evaluate the primary degeneration event and subsequent progressive remodeling that ensues over a timespan that recapitulates the human disease phenotype. Retinas from a TgP347L rabbit model of human dominant RP and wild-type litter mates were harvested over an 8-year span and processed for transmission electron microscope connectomics, immunocytochemistry for a range of macromolecules, and computational molecular phenotyping for small molecules, including transport tracing with D-Asp. Early time points in the TgP347L rabbit recapitulate the established sequence of photoreceptor loss, retinal remodeling, and reprogramming, and also reveal progressive disruptions in Müller cell metabolism, where rather than observing a homogeneous glial population, chaotic metabolic signatures emerge. By 4 years, virtually all remnants of photoreceptors are gone and the neural retina manifests severe cell loss and near complete loss of glutamine synthetase, though glial glutamate transport persists. By 6 years, there is a global &gt;90% neuronal loss. In some regions the retina is devoid of identifiable cells and replaced by unknown debris-like assemblies. Though the 6-year retina does have locations with recognizable neurons, all cell types are drastically reduced in number and some have altered metabolic phenotypes. These results are never seen in wt littermates, including rabbits which are 8 years old. Electron microscopic analysis using wide-field connectomics imaging of the 6-year TgP347L sample demonstrates some structurally normal synapses, indicating that survivor neurons in these regions are not quiescent despite the lack of sensory input for a substantial period of time. These results indicate that, although photoreceptor degeneration is the trigger, retinal remodeling ultimately gives way to neurodegeneration, which is a separate unrelenting disease process independent of the initial insult, closely resembling slow progressive CNS neurodegenerations. Indeed, both metabolic disruption and debris-related degeneration predicts the existence of a persistent neuropathy, and increases in ?-synuclein levels support a proteinopathy component. Remodeling and neurodegeneration progress until the retina is devoid of recognizable cells. There is no stable state into which the retina settles and no cell type is spared. This has profound implications for current therapeutics. There will likely be critical windows for implementation but, ultimately, suspension of neurodegenerative remodeling will be required for long-term success.