Excessive tubulin glutamylation leads to progressive cone-rod dystrophy and loss of outer segment integrity

Abstract

Mutations in Cytosolic Carboxypeptidase-like Protein 5 (CCP5) are associated with vision loss in humans. To decipher the mechanisms behind CCP5-associated blindness, we generated a novel mouse model lacking CCP5. In this model, we found that increased tubulin glutamylation led to progressive cone-rod dystrophy, with cones showing a more pronounced and earlier functional loss than rod photoreceptors. The observed functional reduction was not due to cell death, levels, or the mislocalization of major phototransduction proteins. Instead, the increased tubulin glutamylation caused shortened photoreceptor axonemes and the formation of numerous abnormal membranous whorls that disrupted the integrity of photoreceptor outer segments (OS). Ultimately, excessive tubulin glutamylation led to the progressive loss of photoreceptors, affecting cones more severely than rods. Our results highlight the importance of maintaining tubulin glutamylation for normal photoreceptor function. Furthermore, we demonstrate that murine cone photoreceptors are more sensitive to disrupted tubulin glutamylation levels than rods, suggesting an essential role for axoneme in the structural integrity of the cone outer segment. This study provides valuable insights into the mechanisms of photoreceptor diseases linked to excessive tubulin glutamylation.

Glutamylation imbalance leads to photoreceptor cell degeneration

“…This provided the first link between tubulin polyglutamylation and photoreceptor degeneration in humans. Recently, a mouse model lacking CCP5 showed that hyperglutamylation observed in this mutant leads to photoreceptor cell degeneration with altered outer segments (Aljammal et al, 2024). However, mechanisms of photoreceptor cell degeneration at play are not known.…”