Post-GWAS functional analyses ofCNTNAP5suggests its role in glaucomatous neurodegeneration

Author:

Chakraborty SudiptaORCID,Sarma Jyotishman,Roy Shantanu Saha,Mitra Sukanya,Bagchi Sayani,Das Sankhadip,Saha Sreemoyee,Mahapatra Surajit,Bhattacharjee Samsiddhi,Maulik Mahua,Acharya MoulinathORCID

Abstract

AbstractPrimary angle closure glaucoma (PACG) affects more than 20 million people worldwide, with an increased prevalence in south-east Asia. In a prior haplotype-based GWAS, we identified a novelCNTNAP5genic region, significantly associated with PACG. In the current study, we have extended our perception ofCNTNAP5involvement in glaucomatous neurodegeneration in a zebrafish model, through investigating phenotypic consequences pertinent to retinal degeneration upon knockdown of cntnap5 by translation-blocking morpholinos. While cntnap5 knockdown was successfully validated using an antibody, immunofluorescence followed by western blot analyses in cntnap5-morphant (MO) zebrafish revealed increased expression of acetylated tubulin indicative of perturbed cytoarchitecture of retinal layers. Moreover, significant loss of Nissl substance is observed in the neuro-retinal layers of cntnap5-MO zebrafish eye, indicating neurodegeneration. Additionally, in spontaneous movement behavioural analysis, cntnap5-MO zebrafish have a significantly lower average distance traversed in light phase compared to mismatch-controls, whereas no significant difference was observed in the dark phase, corroborating with vision loss in the cntnap5-MO zebrafish. This study provides the first direct functional evidence of a putative role ofCNTNAP5in visual neurodegeneration.

Publisher

Cold Spring Harbor Laboratory

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