Evidence of an Annexin A4 mediated plasma membrane repair response to biomechanical strain associated with glaucoma pathogenesis. Issue 9 (21st July 2022)

• Record Type: Journal Article
• Authors: Vicic, Nevena; Guo, Xiaoxin; Chan, Darren; Flanagan, John G; Sigal, Ian A.; Sivak, Jeremy M.
• Is Part Of: Journal of cellular physiology. Volume 237:Issue 9(2022)
• Page Start: 3687
• Page End: 3702
• Publication Date: 2022-07-21
• Subjects: Annexins -- ANXA4 -- astrocytes -- biomechanics -- glaucoma -- optic nerve -- plasma membrane repair -- stretch; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30834
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Glaucoma is a common neurodegenerative blinding disease that is closely associated with chronic biomechanical strain at the optic nerve head (ONH). Yet, the cellular injury and mechanosensing mechanisms underlying the resulting damage have remained critically unclear. We previously identified Annexin A4 (ANXA4) from a proteomic analyses of human ONH astrocytes undergoing pathological biomechanical strain that mimics glaucomatous conditions. Annexins are a family of calcium‐dependent phospholipid binding proteins with key functions in plasma membrane repair (PMR); an active mechanism to limit and mend cellular injury that involves membrane and cytoskeletal reorganizations. However, a role for direct membrane damage and PMR has not been well studied in the context of biomechanical strain, such as that associated with glaucoma. Here we report that this moderate strain surprisingly damages cell membranes to increase permeability in a calcium‐dependent manner, and induces rapid aggregation of ANXA4 at injury sites. ANXA4 loss‐of‐function increases permeability, while exogenous ANXA4 reduces it. Furthermore, ANXA4 aggregation is associated with F‐actin dynamics in vitro, and remarkably this interaction and aggregation signature is also observed in the glaucomatous ONH in patient samples. Together these studies link moderate biomechanical strain with direct membrane damage and actin dynamics, and identify an active PMR role for ANXA4 in new model of cell injury associated with glaucoma pathogenesis. Abstract : Glaucoma is a neurodegenerative disease associated with chronic biomechanical strain at the optic nerve head (ONH), often linked to elevated intraocular pressure (IOP). Yet, the mechanism of this tissue damage remains elusive. Annexins have key functions in plasma membrane repair (PMR); a mechanism to limit and mend cellular injury. We report that pathological biomechanical strain damages ONH astrocyte membranes in association with Annexin A4 (ANXA4) function, and propose a model of Ca 2+ ‐induced PMR responses as a component of early glaucoma pathogenesis.