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GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology
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GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology
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Journal Article
GSK3 inhibition reduces ECM production and prevents age-related macular degeneration-like pathology
2024
Overview
Malattia Leventinese/Doyne honeycomb retinal dystrophy (ML/DHRD) is an age-related macular degeneration-like (AMD-like) retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3). To identify new small molecules that reduce F3 production in retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus that enabled simple, sensitive, and high-throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE and non-RPE cells. Low-level, long-term CHIR treatment promoted remodeling of the RPE extracellular matrix, reducing sub-RPE deposit-associated proteins (e.g., amelotin, complement component 3, collagen IV, and fibronectin), while increasing RPE differentiation factors (e.g., tyrosinase, and pigment epithelium-derived factor). In vivo, treatment of 8-month-old R345W+/+ knockin mice with CHIR (25 mg/kg i.p., 1 mo) was well tolerated and significantly reduced R345W F3-associated AMD-like basal laminar deposit number and size, thereby preventing the main pathological feature in these mice. This is an important demonstration of small molecule-based prevention of AMD-like pathology in ML/DHRD mice and may herald a rejuvenation of interest in GSK3 inhibition for the treatment of retinal degenerative diseases, including potentially AMD itself.
Publisher
American Society for Clinical Investigation,American Society for Clinical investigation
Subject
/ Animals
/ CRISPR
/ Extracellular Matrix - drug effects
/ Extracellular Matrix - metabolism
/ Extracellular Matrix Proteins - genetics
/ Extracellular Matrix Proteins - metabolism
/ Glaucoma
/ Glycogen Synthase Kinase 3 - antagonists & inhibitors
/ Glycogen Synthase Kinase 3 - genetics
/ Glycogen Synthase Kinase 3 - metabolism
/ Humans
/ Kinases
/ Macular Degeneration - drug therapy
/ Macular Degeneration - genetics
/ Macular Degeneration - metabolism
/ Macular Degeneration - pathology
/ Mice
/ Mutation
/ Optic Disk Drusen - congenital
/ Peptides
/ Pigment epithelium-derived factor
/ Proteins
/ Retina
/ Retinal Dystrophies - genetics
/ Retinal Dystrophies - metabolism
/ Retinal Dystrophies - pathology
/ Retinal Pigment Epithelium - drug effects
