Glaucoma as a Neurodegenerative Disease Caused by Intrinsic Vulnerability Factors

Highlights

• Traditional concepts in glaucoma involve the neuronal environment and external effects as a source of causative factors

• Molecular profile of retinal ganglion cells in glaucoma patients could make them more vulnerable and/or susceptible to external damage.

• Glaucoma patients share some common genes and features with other neurodegenerative diseases such as Alzheimer disease, Parkinson diseases or amiotropic lateral sclerosis

• Induced pluripotent stem cells (hiPSC)-derived retinal ganglion cells can be generated from glaucoma patients

• Patient´s derived retinal ganglion cells generated from hiPSC could be faithful model to study intrinsic vulnerable factors that contribute to their degeneration.

Abstract

Glaucoma, one of the most common causes of blindness in developing countries today, involves a progressive loss of neural cells in the optic nerve that leads to progressive, irreversible vision loss. Increased intraocular pressure (IOP) presents as a major risk factor for glaucoma, although there exist cases of glaucoma patients with normal IOP that exhibit damage to retinal ganglion cells (RGCs) and the optic nerve. However, treatment approaches have maintained their focus on modifying IOP due to a lack of other modifiable risks factors. Traditional concepts in glaucoma involve the neuronal environment and external effects as a source of causative factors; however, studies have yet to investigate whether the molecular profile of RGCs in glaucoma patients makes them more vulnerable and/or susceptible to external damage. Our hypothesis states that molecular changes at the whole cell, gene expression, and electrophysiological level of the neurons can contribute to their degeneration. Herein, we briefly describe different types of glaucoma and any similarities to different molecular and cellular features of neurodegeneration. To test our hypothesis, we describe human induced pluripotent stem cells (hiPSCs) as a reliable cellular tool to model neurodegenerative aspects of glaucoma to reveal the multiple pathological molecular mechanisms underlying disease development.

Introduction

The retina is a sensory organ that forms the lining of the rear inner surface of the eye and comprises stratified cellular layers supported by a non-neuronal layer of retinal-pigmented epithelium (RPE) cells. Photoreceptors are found within apical layers of the retina adjacent to the RPE and play a central role in the absorption of the light focused by the cornea and lens. After absorption, the retina converts this light into nerve impulses that travel through the layers to the retinal ganglion cells (RGCs) which extend long axons to visual centers in the brain through the optic nerve.

Retinal dystrophies, a heterogeneous group of mostly inherited diseases that entail visual impairment, involve the malfunction or degeneration of retinal cells. Examples of these rare diseases include Leber’s congenital amaurosis (LCA) and retinitis pigmentosa (RP), which mostly affect photoreceptors, or age-related macular degeneration (AMD), which primarily affects RPE cells with subsequent damage to photoreceptors. Optic neuropathies, such as glaucoma, involve the degeneration and subsequent loss of RGCs within the retina, which results in the severing of the important connection between the eye and the brain and leading to visual impairment.

Rough estimates indicate that the global prevalence of glaucoma in the 40-80-year-old population will soon surpass 76 million cases(Tham et al., 2014). Glaucoma patients can present with two major forms of the disease: primary open-angle glaucoma (POAG) or primary angle closure glaucoma (PACG). All of glaucoma severely impact the quality of life, with very limited treatment available to halt or reverse the degeneration of RGCs in the retina. As such, a greater understanding of underlying disease mechanisms and pathology is needed to develop targeted therapeutics and treatments in glaucoma.