Ttll4, short for Tubulin Tyrosine Ligase Like 4, is a polyglutamylase enzyme. Polyglutamylation is a post-translational modification where glutamate residues are added to substrate proteins. Ttll4 is involved in multiple biological pathways related to cytoskeleton organization, neurodegeneration, and cell growth. Its study is crucial as genetic disruption of polyglutamylation can lead to various disorders [1,2,4,5].

In pcd mice, which have a genetic disruption in polyglutamylation, loss of Ttll4 attenuates the degeneration of Purkinje and mitral cells, and partially rescues photoreceptor degeneration and impaired rhodopsin trafficking, indicating its role in neurodegenerative phenotypes [1]. In breast cancer cells, overexpression of Ttll4 is associated with brain metastasis, as it increases polyglutamylation of β-tubulin, alters exosome biogenesis, and affects the adhesion and permeability related to the blood-brain-barrier [3]. In red blood cells, Ttll4-knockout mice show abnormal cytoskeletal organization, with larger average diameters, increased vulnerability to oxidative stress, and macromolecular aggregation of cytoskeletal components [4].

In conclusion, Ttll4 is essential for maintaining proper cytoskeletal architecture in red blood cells, and plays a role in neurodegenerative processes and cancer metastasis. The use of gene-knockout mouse models, such as in pcd mice and Ttll4-knockout mice, has significantly contributed to understanding Ttll4's functions in these disease-related areas.