Abstract
Abstract: :
Purpose and Background: Recent findings demonstrate that ocular neurodegenerative diseases (NDDs) may have the same pathogenic mechanisms as a broad class of other NDDs of the central nervous system. The formation of intracellular protein aggregates which accumulate at centrosome/proteasome in the perinuclear area is central to the pathogenesis of these diseases. Earlier we demonstrated an abnormal synuclein accumulation in the retina of Alzheimer's disease (AD) patients, in the optic nerve of glaucoma patients and rat model of glaucoma. Importantly, a member of the synuclein family implicated in Parkinson's disease, AD and other NDDs is associated with the centrosomes. Here we confirm the association of one of the synuclein members with the centrosome and describe conditions causing its translocation to centrosome/proteasome area. Methods: Two types of antibodies raised to different epitopes of gamma-synuclein : 103 a/p and SC-10698 and antibodies to centrosome proteins for immunohistochemical staining (IHC) and Western blotting (WB) were used. In addition to retinoblastoma Y79 cells we used centrosomes isolated by differential centrifugation from clam oocytes for IHC staining and WB. Results: Gamma synuclein is associated with centrosomes from retinoblastoma Y79 cells, dopaminergic MN9D cells, human astrocytes and bovine retinal pigment epithelium. We confirmed its association with this subcellular organelle in isolated centrosome from Spisula solidissima oocytes. An aster formation assay demonstrates that Y79 cell extract supports microtubule growth at the centrosomes. Gamma synuclein is localized in perinuclear material, but is not associated with centrioles. Conclusions: Aggregation of misfolded proteins leads to impairment of proteasome/ centrosome system. Synuclein aggregation may represent a toxic gain of function, raising the possibility that retinal degeneration and some other eye diseases may share a common pathogenic mechanism with other late onset NDDs.
Keywords: retina: neurochemistry • retinal degenerations: cell biology • retinoblastoma