Retinal Conformational Diseases: From Protein Misfolding to Neurodegeneration

Maintenance of protein homeostasis (proteostasis) is essential for retinal integrity and visual function. The retina is among the most metabolically active tissues in the body, requiring precise control of protein synthesis, folding, trafficking, and degradation. Failure of these processes leads to accumulation of misfolded proteins, formation of toxic oligomers and aggregates, activation of cellular stress responses, and ultimately neuronal degeneration. Such mechanisms are increasingly recognized as central contributors to a broad spectrum of retinal disorders, including inherited retinal dystrophies, age-related macular degeneration, diabetic retinopathy, vitreoretinal amyloidoses, and retinal manifestations of systemic neurodegenerative diseases. Recent evidence indicates that protein aggregation, endoplasmic reticulum stress, impaired autophagy, ubiquitin–proteasome dysfunction, mitochondrial injury, and chronic neuroinflammation are shared pathogenic pathways across these disorders. Inherited forms of retinitis pigmentosa caused by rhodopsin mutations represent prototypical retinal conformational diseases, whereas age-related macular degeneration exhibits feature of a localized amyloidopathy characterized by extracellular deposits containing amyloid-β and other aggregation-prone proteins. Retinal abnormalities associated with Alzheimer's disease, Parkinson's disease, and prion disorders further support the concept that the retina mirrors molecular events occurring in the brain. This review examines current understanding of retinal proteinopathies, emphasizing mechanisms of proteostasis failure, disease-specific protein aggregates, and emerging therapeutic strategies aimed at restoring protein homeostasis. Understanding retinal conformational disorders may facilitate development of novel treatments and establish the retina as an accessible biomarker for neurodegenerative disease.