Exfoliation Syndrome: A Disease of Autophagy and LOXL1 Proteopathy

Abstract

Exfoliation syndrome (XFS) is an age-related disease involving the deposition of aggregated fibrillar material (exfoliation material) at extracellular matrices in tissues that synthesize elastic fibers. Its main morbidity is in the eye, where exfoliation material accumulations form on the surface of the ciliary body, iris, and lens. Exfoliation glaucoma (XFG) occurs in a high proportion of persons with XFS and can be a rapidly progressing disease. Worldwide, XFG accounts for about 25% of open-angle glaucoma cases. XFS and XFG show a sharp age-dependence, similarly to the many age-related diseases classified as aggregopathies. Progress in understanding the cellular bases for XFS/XFG has been slowed by a lack of experimental models. Working with primary human tenon fibroblasts (TF) derived from trabeculectomies of XFG patients and age-matched primary open-glaucoma controls, we found that TF from XFG cells display many of the functional features observed in cells from other protein aggregate diseases, such as Parkinson, Alzheimer, Huntington, and age-related macular degeneration. We have documented defects in lysosomal positioning, microtubule organization, autophagy processing rate, and mitochondrial health. In regard to failure of lysosomal and autophagosome positioning in XFG cells, we have found that XFG TF are unable to establish the transnuclear microtubule organizing center that is required for efficient centripetal vesicular locomotion along microtubules. In regard to potential sources of the autophagy malfunction, we have directed our attention to a potential role of the lysyl oxidase-like 1 protein (LOXL1), the elastic fiber catalyst that displays variant-dependent association with risk for XFG. Our experiments show that (a) in XFG cells, a substantial fraction of LOXL1 is processed for degradation by the autophagic system; (b) most of the LOXL1 N-terminus domain exists in a highly disordered state, a condition known to greatly increase the frequency of polypeptide misfolding; (c) that maximum misfolding occurs at amino acid position 153, the location of the high risk variant G153D; and (d) that replacement of glycine (G) by aspartate (D) there results in a substantial decrease in disorder within the 20 amino acid surrounding domain. Finally, we show that clusterin, a protein that can be induced by the presence of intracellular, or extracellular aggregates, is uniformly overexpressed in XFG TF. The implications of our results for a theory relating XFG to cellular aggregopathy are discussed.

RNA Sequencing of Lens Capsular Epithelium Implicates Novel Pathways in Pseudoexfoliation Syndrome

“…Although the autophagy gene set was not enriched in the current study ( P = 0.79), several autophagy genes were differentially expressed, providing further suggestion that disordered autophagy may be relevant to PEX. 58 By contrast, we did not observe expression changes in extracellular matrix genes including LTBP1 , LTBP2 , TIMP1 , and TIMP2 , which have been demonstrated to exhibit differential expression in PEX tissues. 27 , 28 , 35 Reasons for differences between these results and the current data are unclear.…”

“…In parallel to genetic investigations of PEX which have identified multiple disease-associated risk loci, 10 – 19 biological studies have demonstrated that perturbations in physiological processes including oxidative phosphorylation, 56 , 57 autophagic flux, 51 , 58 and the unfolded protein response 47 may contribute to the PEX disease process. Furthermore, latitudinal differences in PEX prevalence have led to hypotheses that environmental exposures, such as ultraviolet light, may contribute to the disease.…”

Dysregulated Retinoic Acid Signaling in the Pathogenesis of Pseudoexfoliation Syndrome

“…In conclusion, the findings of this study provided evidence of a link between PEX-associated fibrosis and impaired RA signaling in ocular tissues which may be influenced by genetic and environmental factors. Dysregulated RA signaling has the potential to contribute to PEX pathogenesis through multiple downstream pathways which are known to be involved in PEX pathogenesis, including TGF-β1 and Wnt signaling pathways, autophagy, and mitochondrial dysfunction [ 3 , 56 ]. The interaction of the RA signaling pathway with all these pathways is well documented [ 57 , 58 , 59 ].…”

Macula Vessel Density and Foveal Avascular Zone Parameters in Exfoliation Glaucoma Compared to Primary Open-Angle Glaucoma

“…Over time, the XFM pileup appears to nibble away at the endothelial cells that line blood vessels, as well as the pericytes, contractile cells that wrap around the endothelial cells and help give blood vessel walls strength and flexibility; these cellular changes may impact vascular tissue around the body. XFS may also be associated with compromised autophagy of cellular waste, and this may lead to buildup of misfolded proteins 56. This abnormality may result in oxidative stress leading to vascular pathology.…”