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Christopher Laver, Joanne A Matsubara; Interspecific divergence of essential triad ribbon synapse protein, pikachurin – implications for preclinical trials in photoreceptor transplantation therapy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4437.
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© ARVO (1962-2015); The Authors (2016-present)
As photoreceptor transplantation rapidly moves closer to the clinic, the importance of verifying graft efficacy in animal models may have unforeseen xenogeneic barriers. Although conspecific photoreceptor transplants have clearly resulted in functional synaptogenesis, such unambiguous findings (ruling out false-positives due to viral graft labeling or fusion) have not yet been shown for discordant xenografts. From this, a fundamental question should be raised: is xenosynaptogenesis likely between human photoreceptors and mouse retina? The triad ribbon synapse between photoreceptor, bipolar, and horizontal cells is unique and contains a trans-synaptic protein essential and specific to its formation and function – pikachurin. This protein is only produced by photoreceptors and binds to an unknown target on the bipolar cell post-synaptic terminus via its N-terminal domains. Thus, could interspecific structural divergence be present that may inhibit this essential trans-synaptic handshake?
In an effort to address this question computationally, we compared pikachurin across placental mammals (1-to-1 orthologs of 35 species) using phylogenetic analysis, including dN/dS measurements for positive selection (via PhyML and HyPhy methods), and at the tertiary structural level using predictive modeling (via Phyre2 and DeepAlign methods).
Sequence similarity for human and mouse pikachurin were 77% and 94% in the N- and C-terminal domains, respectively. This produced large structural divergence (41% length of alignment) in the predicted models and was mainly localized to the N-terminal domains. Selection analysis revealed strong positive (diversifying) selection acting on the N-terminal domains (37 of the 61 positively selected codons, PSCs, were found in this region). Negative (purifying) selection was seen in the C-terminal domains, with the exception of 20/24 C-terminal PSCs residing in a single LG-domain. Together, these data indicate adaptive structural divergence in the N-terminus among placental mammals.
Given the critical role of pikachurin in photoreceptor graft-to-host synaptogenesis and function, and its structural dissimilarity predicted between humans and mice, particularly in the xeno-interaction domains, it is important to consider these factors when designing future preclinical transplantation studies.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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