The study "Dysregulation of septin cytoskeletal organization in the trabecular meshwork contributes to ocular hypertension," led by Rupalatha Maddala, PhD. The study published in the December 6, 2024 issue of Journal of Cell Science Insight focuses on a protein structure called the septin cytoskeleton, which may have the potential to be a target for lowering intraocular pressure.
Ocular hypertension, believed to result partly from increased contractile activity, cell adhesive interactions, and stiffness within the trabecular meshwork (TM), is a major risk factor for glaucoma, a leading cause of blindness. However, the identity of molecular mechanisms governing organization of actomyosin and cell adhesive interactions in the TM remains limited. Based on our previous findings, in which proteomics analyses revealed elevated levels of septins, including septin-9 in human TM cells treated with the ocular hypertensive agent dexamethasone, here, we evaluated the effects of septin-9 overexpression, deficiency, and pharmacological targeting in TM cells. These studies demonstrated a profound impact on actomyosin organization, cell adhesion, contraction, and phagocytosis. Overexpression raised intraocular pressure (IOP) in mice, while inhibition increased cell permeability. In addition, we replicated a significant association between a common variant (rs9038) in SEPT9 with IOP in the Genetic Epidemiology Research on Adult Healthy and Aging (GERA) cohort. Collectively, these data reveal a link between dysregulated septin cytoskeletal organization in the TM and increased IOP, likely due to enhanced cell contraction, adhesive interactions, and fibrotic activity. This suggests that targeting the septin cytoskeleton could offer a novel approach for lowering IOP in patients with glaucoma.
The cover image of their report shows how septin-7 (a specific protein) interacts with other cell structures in the trabecular meshwork. This interaction is visualized using different colors: red for actin stress fibers and blue for cell nuclei
Duke Co-authors include Pallavi Gorijavolu, Levi Lankford, Nikolai Skiba, PhD. Pratap Challa, MD, and Ponugoti Rao, PhD.