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Eugenia Gurevich, Xiufeng Song, Jungwon Seo, Faiza Baameur, Sergey Vishnivetskiy, Qiuyan Chen, Miyeon Kim, Jeannie Chen, Wayne Hubbell, Vsevolod Gurevich; Robust self-association of arrestin-1 is a neuroprotective mechanism. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2456.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the biological role of arrestin-1 self-association.
Retinal morphology and the health of rod photoreceptors in mice of different ages expressing wild type (WT) arrestin-1 and mutant with impaired self-association was compared.
Arrestin-1 binds light-activated phosphorhodopsin and ensures timely signal shutoff. Arrestin-1 self-association is conserved in at least three mammalian species, but its biological role remains obscure. We found that high expression of arrestin-1 mutant with impaired oligomerization, but not of WT arrestin-1 that robustly oligomerizes, results in progressive rod degeneration via apoptosis. Synaptic terminals of rods are adversely affected earlier than other cell compartments. Dark rearing does not prevent mutant-induced cell death, ruling out the role of arrestin-rhodopsin complexes. WT arrestin-1 co-expressed with the mutant delays retinal degeneration, likely by forming mixed oligomers.
Monomeric arrestin-1 is cytotoxic, and it likely acquired propensity to oligomerize to reduce the concentration of the monomer in the cell. This finding suggests that cones express the bulk of their arrestin complement (~98%) in the form of arrestin-1 because cone-specific arrestin-4 is naturally oligomerization-deficient and therefore likely cytotoxic. The results also suggest that arrestin-1 binding to microtubules largely serves to minimize free monomer in the cell body, rather than to localize arrestin-1 away from the outer segment in the dark.
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