title: Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease.
abstract: Aggregation of α-synuclein (α-syn) in neurons of the substantia nigra is diagnostic of Parkinson's disease (PD), a neuro-motor disorder with prominent visual symptoms. Here, we demonstrate that α-syn, the principal protein involved in the pathogenesis of PD, is expressed widely in the neuroretina, and facilitates the uptake of transferrin-bound iron (Tf-Fe) by retinal pigment epithelial (RPE) cells that form the outer blood-retinal barrier. Absence of α-syn in knock-out mice (α-syn(-/-)) resulted in down-regulation of ferritin in the neuroretina, indicating depletion of cellular iron stores. A similar phenotype of iron deficiency was observed in the spleen, femur, and brain tissue of α-syn(-)(/-) mice, organs that utilize mainly Tf-Fe for their metabolic needs. The liver and kidney, organs that take up significant amounts of non-Tf-bound iron (NTBI), showed minimal change. Evaluation of the underlying mechanism in the human RPE47 cell line suggested a prominent role of α-syn in the uptake of Tf-Fe by modulating the endocytosis and recycling of transferrin (Tf)/transferrin-receptor (TfR) complex. Down-regulation of α-syn in RPE cells by RNAi resulted in the accumulation of Tf/TfR complex in common recycling endosomes (CREs), indicating disruption of recycling to the plasma membrane. Over-expression of exogenous α-syn in RPE cells, on the other hand, up-regulated ferritin and TfR expression. Interestingly, exposure to exogenous iron increased membrane association and co-localization of α-syn with TfR, supporting its role in iron uptake by the Tf/TfR complex. Together with our observations indicating basolateral expression of α-syn and TfR on RPE cells in vivo, this study reveals a novel function of α-syn in the uptake of Tf-Fe by the neuroretina. It is likely that retinal iron dyshomeostasis due to impaired or altered function of α-syn contributes to the visual symptoms associated with PD.
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Shounak
authors.initials: S
authors.lastname: Baksi
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Ajai K
authors.initials: AK
authors.lastname: Tripathi
authors.affiliation: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: neena.singh@case.edu.
authors.forename: Neena
authors.initials: N
authors.lastname: Singh
mesh_terms: D000818:Animals; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D010300:Parkinson Disease; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D014168:Transferrin / Q000378:metabolism*; D051844:alpha-Synuclein / Q000502:physiology*
chemical_list: D014168:Transferrin; D051844:alpha-Synuclein; D007501:Iron
keywords: Parkinson's disease; Retina; Retinal pigment epithelial cells; Transferrin receptor; Transferrin-bound iron; α-Synuclein