Abstract
BackgroundAging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Among many contributing factors to age-related deterioration of neurons is an insufficient activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) in response to cellular stress. X-box binding protein 1 (XBP1) is a major component of the UPR and is essential for maintaining protein homeostasis and reducing cellular stresses. Herein, we investigate the role of XBP1 in maintaining morphological and functional integrity in retinal neurons during adulthood and the early stages of aging.MethodsThe basal and induced levels of XBP1 activation in the retina were measured in young adult and aged mice. Conditional knockout (cKO) of XBP1 in retinal neurons was achieved by crossing XBP1 floxed mice with a retina specific Cre-recombinase line (Chx10-Cre). Retinal morphology, neuronal populations including photoreceptors, bipolar cells, and retinal ganglion cells (RGCs), synaptic structure, and microglial activation were examined with immunohistochemistry and staining of retinal sections. Retinal function was evaluated with light-adapted (photopic) and dark adapted (scotopic) electroretinograms. Retinal mitochondrial function and metabolism was assessed by Seahorse XFe24 Extracellular Flux Analyzer.ResultsThe retinas of aged wild type (WT) mice display a significantly reduced basal level of Xbp1s and compromised activation of ER stress response. In XBP1 cKO mice, significant structural degeneration of the retina, evidenced by thinning of retinal layers and a loss of RGCs, and functional defects indicated by diminished photopic and scotopic ERG b-waves are observed at the age of 12–14 months. Furthermore, discontinuous and disorganized synaptic laminae, colocalized with activated microglia, in the inner plexiform layer is found in the XBP1 cKO retinas. In addition, cKO mice demonstrate a significant increase in ectopic synapses between bipolar cells and photoreceptors, which is strikingly similar to WT mice at 20–24 months of age. These changes are associated with defective retinal glycolysis while mitochondrial respiratory function appears normal in the cKO retina.ConclusionsXBP1 cKO mice at 12–14 months of age show significant structural, functional, and metabolic deficits that closely resemble WT mice twice that age. Our findings suggest that the absence of XBP1, a critical component of the UPR, accelerates age-related retinal neurodegeneration.
Highlights
Aging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system
Compromised endoplasmic reticulum (ER) stress response in the retina of aged wild type mice We examined the mRNA level of Unfolded Protein Response (UPR) genes including X-box binding protein 1 (XBP1), ATF4, ATF6, p58ipk, and CHOP in young adult (4 months old) and aged (20–24 months old) XBP1 fl/fl mouse retina using reverse transcription quantitative PCR
These results suggest that the UPR of aged retina is more biased towards the CHOP pathway, generally associated with apoptosis, than the XBP1s pathway, generally associated with maintaining the ER homeostasis
Summary
Aging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Bipolar cells in aged retinas extend dendrites into the outer nuclear layer (ONL) to form ectopic synapses with retracted rod axons [2, 3]. These changes are recapitulated in mice with deletions of either LKB1 or AMPK, key metabolic pathway controlling proteins, in subsets of retinal cells at just two months of age [4]. These findings indicate that disturbance in retinal metabolism is likely behind some age-related deterioration in retinal neurons.
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