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Editors Selection IGR 20-4
Basic Science: Cellular changes in trabecular cells
Comment by Nils Loewen & Alicja Strzalkowska on:
82397 Prion protein modulates endothelial to mesenchyme-like transition in trabecular meshwork cells: Implications for primary open angle glaucoma, Ashok A; Kang MH; Wise AS et al., Scientific reports, 2019; 9: 13090
Over-activation of the ROCK pathway causes cytoskeletal changes in trabecular meshwork cells (stress fibers, increased stiffness) and leads to IOP elevation, a mechanism that is now exploited by new therapeutics.1-3 Ashok et al. have a long history of investigating the role and dysfunction of the prion protein (PrPc). Their more recent interest includes PrPc's participation in iron metabolism of the posterior4 and anterior segment of the eye.5 In this study, the authors describe how PrPC induces an endothelium-to-mesenchyme-like transition and argue that this is similar to the epithelium-to-mesenchyme transition that PrPC can induce in neuronal cells through β1-integrin and Rho-ROCK activation.6-9 The authors do not explain why they think endo- and epithelial function and origins are interchangeable, however. The key pathogenic event in all prion disorders is a change in the conformation of PrPC to a β-sheet rich PrP-scrapie (PrPSc) isoform and could also be at fault here.
The authors performed an impressive array of experiments in three different species (bovine, human, murine) including PrP-knockout mice. Downregulation of PrPc activated the Rho/ROCK pathway and led to aggregation of β1-integrin, upregulation of fibronectin, collagen 1A, α-SMA and myocilin causing IOP to increase.
It is tempting to follow the line of thought by the authors that puts prions and PrPc not only central to neurodegeneration in glaucoma, but also to outflow failure. Both was already suggested by the discoverer of prions, Stanley Prusiner, in 2008 (personal communication). The authors propose a mechanism that incorrectly generalizes that POAG patients have an elevated level of matrix metallo-proteinases (MMPs), which cleave PrPc and thereby further worsen the TM outflow failure. Although there are clinicians on the team, the authors fail to realize that the same MMPs (MMP 2 and 9) they believe to be important in their model of IOP elevation, are actually therapeutically upregulated by laser trabeculoplasty to lower IOP.10 Patients with prion diseases are also not known to have elevated eye pressures (but do more frequently get tonography11), even though prions are typically present in ocular tissue.12 Conversely, glaucoma patients do not have more PrPc.13
References
- Wang K, Read AT, Sulchek T, Ethier CR. Trabecular meshwork stiffness in glaucoma. Exp Eye Res. 2017;158:3-12.
- Dang Y, et al. A porcine ex vivo model of pigmentary glaucoma. Sci Rep. 2018;8:5468.
- Dang Y, et al. RKI-1447, a Rho kinase inhibitor, causes ocular hypotension, actin stress fiber disruption, and increased phagocytosis. Graefes Arch Clin Exp Ophthalmol. 2018; doi:10.1007/s00417-018-4175-6.
- Asthana A, et al. Prion protein facilitates retinal iron uptake and is cleaved at the β-site: Implications for retinal iron homeostasis in prion disorders. Sci Rep. 2017;7:9600.
- Ashok A, et al. Prion protein modulates iron transport in the anterior segment: Implications for ocular iron homeostasis and prion transmission. Exp Eye Res. 2018;175:1-13.
- Alleaume-Butaux A, et al. Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation. PLoS Pathog. 2015;11, e1005073.
- Kim HJ, et al. Regulation of RhoA activity by the cellular prion protein. Cell Death Dis. 2017;8, e2668.
- Mehrabian M, Ehsani S, Schmitt-Ulms G. An emerging role of the cellular prion protein as a modulator of a morphogenetic program underlying epithelial-tomesenchymal transition. Front Cell Dev Biol. 2014;2:53.
- Ghodrati F, et al. The prion protein is embedded in a molecular environment that modulates transforming growth factor β and integrin signaling. Sci Rep. 2018;8:8654.
- Parshley DE, Bradley JM, Samples JR, et al. Early changes in matrix metalloproteinases and inhibitors after in vitro laser treatment to the trabecular meshwork. Curr Eye Res. 1995;14:537-544.
- Davanipour Z, Alter M, Sobel E, Asher D. De-mentia: Possible Transmission by Trauma, Surgery, Sutures, and Tonometers: PP266. Neurology. 1985;35.
- Head MW, et al. Prion protein accumulation in eyes of patients with sporadic and variant Creutzfeldt-Jakob disease. Invest Oph-thalmol Vis Sci. 2003;44:342-346.
- Lindner E, et al. Cellular prion protein on human leucocytes is associated with iron metabolism. In PRION vol. 13, pp. 24-24 (TAYLOR & FRANCIS INC 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA, 2019).
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