Artikel
Glycan analyses of rd1 mouse retinal proteins (a model of retinitis pigmentosa) indicates a need for therapy to hyper-glycosylate mutated synaptic proteins and to improve outcome of current gene therapies
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Veröffentlicht: | 5. Februar 2020 |
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Gliederung
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Introduction: Retinal degeneration1 (rd1) mouse, an animal model of Retinitis Pigmentosa, (RP), shows mutation in β-subunit of cGMP phosphodiesterase-6 (PDE-6) gene and is associated with modified expression of ~60 other genes affecting transcription, cell-adhesion/proliferation. Deficiency of PDE-6 elevates cGMP and Ca2+ ion levels in the rod photoreceptors with loss of ~90% rods in rd1 mice. rd1 mice retinal neurons express mutated gene protein(s) and have modified ribbon synapse connectivity due to hypo-glycosylation of proteins. Such neuronal changes lead to blindness.
Current gene therapies for mutated glycoproteins are inadequate as protein hypo-glycosylation processes have not been taken into consideration. Correct post-translation glycosylation of proteins, is achieved by a balance in glycosyl -transferase/-hydrolase activities. This report reviews dynamic changes in the nature/extent of retinal protein glycans which participate in retinal- function/development/degeneration; and highlights significance of glycans and glycosyl-transferases for success of the current gene therapies.
Material & Methods: Comparative dynamic changes in the nature/extent of glycosylation of retinal proteins, from neonatal wt and rd1 mice, were profiled/quantified by lectin microarray analyses and compared for their role in retinal function/development/degeneration as reported in literature.
Results: (See [1], [2], [3]): Age/mutation dependent relative and dynamic changes in high-mannose- and GlcNAc-, Siaα2-3Galβ1-4GlcNAc-glycans associated with wt and rd1 retinal proteins suggest hypo-glycosylation of retinal proteins which adversely influence their participation in the retinal function/development/degeneration. Degree of mannosylation and sialylation with Siaα2-3Gal (not Siaα2-6Gal) possibly regulates ERG function, whereas decreased core fucosylation and increased outer bisecting GlcNAc glucosylation/galactosylation was correlated with retinal degeneration. Functional/dynamic and quantitative differences observed in wt and rd1 retinal protein glycans suggested that rd1 mutation(s) create imbalance in the glycosyl-transferases/-hydrolases activities which modifies glycosylation of synaptic proteins.
Conclusions: Studies on mutation in glycosyl-transferases to achieve hyper-glycosylation of retinal synaptic proteins in rd1 mouse model of RP and to improve the efficacy of current gene therapies are needed.
Acknowledgement: To Karin Sandqvists Stiftelse, Stockholm (Sweden) for a travel grant.
Keywords: Mice, Glycans, Retinal-Development/Degeneration/Function, Gene-Therapy
References
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- Ahuja S. Lectin microarray profiling and relative quantification of glycome associated with proteins of neonatal wt and rd1 mice retinae. Invest Ophthalmol Vis Sci. 2013;54(5):3272–80. DOI: 10.1167/iovs.12-11363
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- Ahuja S. Determination of Dynamic Changes in the Nature and Biosynthesis of Glycome of wt and rd1 Mice Retinae by Lectin Microarray Analysis. Invest Ophthalmol Vis Sci. 2014;55(2):654–7. DOI: 10.1167/iovs.13-13783
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- Ahuja S. Possible role of sialylation of retinal protein glycans in the regulation of electroretinogram response in mice. Int J Ophthalmol. 2017 Aug 18;10(8):1217-22. DOI: 10.18240/ijo.2017.08.05. eCollection 2017.