alpha-synuclein and Macular-Degeneration

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.

Topics: alpha-Synuclein; Autophagy; Exosomes; Humans; Macular Degeneration; Retina

Drusen are a hallmark of eyes affected by age-related macular degeneration. In previous study, a conformational-specific antibody showed drusen to contain nonfibrillar amyloid structures. The current study was undertaken to assess the presence of additional amyloid structures in drusen.. Sections from human donor eyes were reacted with M204, a monoclonal antibody that recognizes nonfibrillar oligomers; OC, a polyclonal antibody that recognizes amyloid fibrils of various molecular weights; and WO1 and WO2, monoclonal antibodies that are specifically reactive to mature amyloid fibrils. Electron microscopy was used as an independent means of investigating the presence of amyloid fibrils in drusen.. The presence of nonfibrillar oligomers was verified using the M204 antibody. OC and WO antibodies stained a wide spectrum of vesicular structures. OC reactivity showed extensive overlap with Abeta immunoreactivity, whereas a partial overlap was seen between Abeta reactivity and that of the WO antibodies. The presence of amyloid fibrils was also visualized by electron microscopy.. These data reveal the presence of a wide spectrum of amyloid structures in drusen. The results are significant, given that specific conformational forms of amyloid are known to be pathogenic in a variety of neurodegenerative diseases. Deposition of these structures may lead to local toxicity of the retinal pigmented epithelium or induction of local inflammatory events that contribute to drusen biogenesis and the pathogenesis of AMD.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal; Humans; Macular Degeneration; Microscopy, Confocal; Microscopy, Immunoelectron; Pigment Epithelium of Eye; Prions; Retinal Drusen; Tissue Donors

Parkinson's disease (PD) patients show a characteristic loss of motor control caused by the degeneration of dopaminergic neurons. Mutations in the genes that encode alpha-synuclein and parkin have been linked to inherited forms of this disease. The parkin protein functions as a ubiquitin ligase that targets proteins for degradation. Expression of isoforms of human alpha-synuclein in the Drosophila melanogaster nervous system forms the basis of an excellent genetic model that recapitulates phenotypic and behavioural features of PD. Using this model, we analysed the effect of parkin co-expression on the climbing ability of aging flies, their life span, and their retinal degeneration. We have determined that co-expression of parkin can suppress phenotypes caused by expression of mutant alpha-synuclein. In the developing eye, parkin reduces retinal degeneration. When co-expressed in the dopaminergic neurons, the ability to climb is extended over time. If conserved in humans, we suggest that upregulation of parkin may prove a method of suppression for PD induced by mutant forms of alpha-synuclein.

Topics: alpha-Synuclein; Animals; Animals, Genetically Modified; Disease Models, Animal; Dopamine; Down-Regulation; Drosophila; Drosophila Proteins; Female; Gene Expression; Macular Degeneration; Male; Motor Activity; Mutant Proteins; Neurons; Parkinson Disease; Ubiquitin-Protein Ligases