gms | German Medical Science

7th International Symposium on AMD: Age-related Macular Degeneration – Understanding Pathogenetic Mechanisms of Disease

20.09. - 21.09.2019, Baden-Baden

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

Meeting Abstract

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  • Satpal Ahuja - Lund/S

7th International Symposium on AMD: Age-related Macular Degeneration - Understanding Pathogenetic Mechanisms of Disease. Baden-Baden, 20.-21.09.2019. Düsseldorf: German Medical Science GMS Publishing House; 2020. Doc19amd44

doi: 10.3205/19amd44, urn:nbn:de:0183-19amd441

Veröffentlicht: 5. Februar 2020

© 2020 Ahuja.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

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

1.
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 Externer Link
2.
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 Externer Link
3.
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. Externer Link