Mechanism behind blindness linked to excess glutamylation

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Abstract Post-translational modification of proteins play an important role in increasing the complexity and functional diversity of limited set of proteins expressed in the cell. One such interesting and highly significant chemical modification is glutamylation. Protein glutamylation is a post-translational modification (PTM) that adds glutamate to one of the glutamic residues in the C terminus of the protein. Protein Glutamylation is dynamic and controlled by repertoire of enzymes, tubulin tyrosine ligase-Like (TTLLs) that add glutamyl group, and by another family of enzymes called cytosolic carboxypeptidase (CCPs or AGBLs) that cleaves the glutamate. Mutation in one member of deglutamylase family, AGBL5 is linked to inherited blindness in humans. While glutamylation is thought to aid in trafficking of proteins, the mechanism behind the blindness linked to excess glutamylation in not known. This proposal aims to investigate the consequences of excess glutamylation in the rod and cone photoreceptors with a mouse model that lacks AGBL5. This fellowship will help reach my long-term goal of understanding mechanisms behind diseases that afflict humans. The findings from this study will advance our understanding of the mechanism underlying the genetic blindness and human health.