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M. M. Abd-El-Barr, K. Sykoudis, S. Andrabi, E. R. Eichers, P. L. Tan, J. H. Wilson, N. Katsanis, J. R. Lupski, S. M. Wu; The Bardet Biedl Protein BBS4 is Required for Light-Dependent Protein Transport in Photoreceptors. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2504.
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© ARVO (1962-2015); The Authors (2016-present)
To understand the role of the Bardet Biedl Syndrome Protein (BBS4)in stabilizing microtubule structure, protein transport and photoreceptor degeneration in the mammalian retina.
Transmission Electron Microscopy (TEM), Electroretinography (ERG), Immunohistochemistry and Western Blotting were used to examine Bbs4-null and wild type littermates.
1) TEM of 4 week old mice retinas revealed that Bbs4-null mice had shortened outer segments, however the ‘9+0’ microtubule structure of the connecting cilium and basal bodies were normal. 2) BBS4 protein is localized to photoreceptor inner segments and the synaptic terminals. 3) In Bbs4-null mice, we observed impaired sequestration of transducin to the outer segment in the dark and impaired light-induced movement of arrestin to the outer segment. 4) Transport of structural proteins such as Peripherin/rds and rom-1 to the outer segment is not affected in Bbs4-null mice. 5) Western blot analysis of whole retinas detects full-length phototransduction protein in the Bbs4-null mice, but at decreased levels. 6) Although the a-wave amplitudes were decreased in Bbs4-null mice, fitting the a-wave to a Lamb-Pugh fit yielded a very similar amplification constant. 7) Photoreceptor synaptic terminal structure and vesicular proteins are normal, but decreased b-to-a wave ratios at lower light intensities (<100 φ/rod) are found in Bbs4-null mice, suggesting a possible role of the BBS4 protein in modulating photoreceptor output synapses.
Our results suggest that the BBS4 protein is not required for stabilization of microtubule structures, but is required for the transport of phototransduction proteins. The proper localization of structural proteins suggests that there are at least two mechanisms for protein transport to the outer segments. Phototransduction proteins appear to be transported via a BBS4-dependent pathway, while structural proteins are transported in a BBS4-independent pathway. Our data suggest that photoreceptor degeneration in BBS4 is likely to be due to transport defects of phototransduction proteins, rather than defects in protein function, as the proteins are shown to be full length and capable of initiating phototransduction. We also demonstrate a putative role of BBS4 in photoreceptor synaptic transmission.
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