Dr Dirk Booysen
August 2026
Ever wondered what happens to the retinal ganglion cells in glaucoma and other optic neuropathies?
Peer-reviewed literature established that RGC loss occurs primarily via programmed cell death (apoptosis) rather than necrosis, driven by several interconnecting stress pathways. These pathways can be broadly classified as: Biomechanical, ischemic, and inflammatory.
- Mechanical Compression & Axonal Transport Deficit
- Elevated intraocular pressure (IOP) or biomechanical strain at the lamina cribrosa causes mechanical shearing of RGC axons.
- Consequence: Disruption of anterograde and retrograde axoplasmic transport starves the cell body of vital neurotrophins, specifically brain-derived neurotrophic factor (BDNF), triggering intrinsic apoptotic cascades (Quigley et al., Investigative Ophthalmology & Visual Science).
- Excitotoxicity & Glutamate Dysregulation
- Ischemic or mechanical injury induces extracellular accumulation of glutamate in the retina.
- Consequence: Overstimulation of N-methyl-D-aspartate (NMDA) receptors drive massive extracellular calcium (Ca2+) influx into RGCs. Pathological intracellular calcium overloading activates calpains and caspases, executing apoptotic death (Sucher et al., Vision Research).
- Mitochondrial Dysfunction & Metabolic Vulnerability
- RGC unmyelinated intra-retinal axons have exceptionally high metabolic demands.
- Consequence: IOP-induced ischemia and strain induce mitochondrial permeability transition pore (mPTP) opening, depleting ATP and releasing cytochrome c into the cytosol. Cytochrome c binds Apaf-1 to form the apoptosome, activating executioner Caspase-3 (Nickells et al., Progress in Brain Research).
- Neuroinflammation & Glial Reactivity
- Structural stress activates surrounding retinal microglia and astrocytes.
- Consequence: Reactive astrocytes and activated microglia release pro-inflammatory cytokines (TNF-α, IL-1β) and reactive oxygen species (ROS), accelerating secondary degeneration of neighboring, previously uninjured RGCs (Tezel et al., Progress in Retinal and Eye Research).
What about Etiologies Outside Glaucoma?
| Pathology | Primary Trigger Mechanism | Molecular Endpoint |
|---|---|---|
| Leber Hereditary Optic Neuropathy (LHON) | Point mutations in mitochondrial DNA (ND1, ND4, ND6 genes) | Complex I defect → ROS overload → Focal RGC apoptosis |
| Ischemic Optic Neuropathy (AION/NAION) | Hypoperfusion/infarction of short posterior ciliary arteries | Hypoxia → Rapid ATP depletion → Mixed necrosis/apoptosis |
| Optic Neuritis (MS-related) | Autoimmune-mediated demyelination of RGC axons | Axonal membrane disruption → Secondary soma loss |