A perspective on the role of the extracellular matrix in progressive retinal degenerative disorders

Abstract

Progressive inherited retinal degenerative disorders (PIRDDs) are the leading cause of blindness in developed countries, with AMD and RP constituting the majority of PIRDDs. Currently, over 8 million Americans have PIRDDs, and that number is estimated to drastically increase by the end of this decade. Although a mutant protein is expressed starting early during retinal development in patients with PIRDDs, symptoms of retinal degeneration do not manifest until much later. Historically, research has focused on understanding the role a mutation has in the function of a protein and what role the mutant protein has in the disease process. However, it remains unknown why the disease, irrespective of the mutation, manifests clinically much later in life, while cellular indicators of disease (e.g., accumulation of toxic protein products and cell death) occur throughout early and middle life. Herein, we propose that there exists a time point at which the degenerative process is accelerated, leading to the appearance of clinical symptoms. This point is defined by structural disruptions of the extracellular matrix (ECM). Death of a critical number of ECM-maintaining mutant protein-expressing retinal cells contributes to that break point in the degenerative process. Therefore, it is important to understand the changes occurring at the ECM during PIRDDs and to take that into account when therapeutic approaches are designed.

Keywords: aging; extracellular matrix; retinal degeneration.

Figure

Changes in ERG responses as a function of age (solid line). As humans age, there is a gradual decline in ERG responses until age 55 years, followed by rapid decline until ERG responses drop to approximately 50% of that of young cohorts by age 69 years for rods and by age 70 years for cones. Shown are hypothetical ERG responses from patients with PIRDDs as a function of age, without any therapeutic interventions (squares); with one form of therapy such as gene, cell, or neurotrophic therapy (circles); or with combinational therapy (stars). @, Age-dependent critical point; #, age when PIRDDs-associated changes become prominent. This can shift depending upon the rate of degeneration.