In the course of age-related macular degeneration (AMD) as well as in multiple retinal disorders protein aggregates are described at various levels in the retina. In AMD this fills the space between retinal pigment epithelium (RPE) in the form of drusen, which contains amyloid and other protein aggregates along with lipids. Nonetheless, in very advanced stages of AMD, as well as in other retinal pathologies and early on in retinitis pigmentosa, a number of neuronal inclusions, which stain for α-synuclein spreads all over the retinal layers. Thus, an early or later defect in the clearance of α-synuclein may represent a final common pathway to these phenomena. The physiological clearance of α-synuclein is provided by the autophagy machinery starting at the level of the RPE and occurring throughout the retina. Such a process is also involved in the clearance of melanin-dependent toxic metabolites under the effects of different wavelengths and the stimulatory activity of the sympathetic nervous system. In search for the occurrence of these culprits, here we report the presence of α-synuclein in the retina combined with exosomal detection to document the presence of a α-synuclein spreading apparatus. This was correlated with the occurrence of autophagy markers throughout retinal layers, along with sympathetic innervation, which in turn was related to melanin content.