Ttll1, short for Tubulin tyrosine ligase-like 1, is a key enzyme in the tubulin tyrosine ligase superfamily. It is involved in the posttranslational polyglutamylation of tubulin in axonemal microtubules within cilia and flagella. Polyglutamylation is a dynamic process that impacts microtubule functions, and Ttll1 is crucial for maintaining the balance of this modification [4,6]. Genetic models, such as gene knockout mice, have been instrumental in studying its function.

In pcd mice (mutant for the Nna1/CCP1 gene), loss of Ttll1 attenuates Purkinje cell loss and function, reduces olfactory bulb mitral cell death, and retinal photoreceptor degeneration. This indicates Ttll1's role in neurodegenerative phenotypes associated with disrupted polyglutamylation. In addition, Ttll1 deficiency in pcd mice also rescues impaired rhodopsin trafficking to the rod outer segment, which likely represents the causal defect leading to photoreceptor degeneration [1]. Ttll1-knockout mice also show abnormal behaviors and increased glutamate levels in the brain, suggesting its role in regulating glutamate concentration [2]. Moreover, in the context of axon growth, Netrin-1-induced axonal growth rate increases depend on Ttll1-mediated microtubule polyglutamylation [3]. In Trypanosoma brucei, Ttll1 is essential for the integrity of the microtubule structure at the cell pole [5]. And in mice, Ttll1 deficiency leads to chronic rhinosinusitis and abnormal spermatid flagella development, highlighting its importance in ciliary and flagellar functions [6].

In summary, Ttll1 is essential for multiple biological processes, particularly those related to microtubule-associated functions such as ciliary and flagellar motility, axon growth, and neuronal function. Studies using Ttll1 knockout mouse models have significantly advanced our understanding of its role in neurodegenerative diseases, abnormal behaviors, and ciliary-related disorders, providing insights into potential therapeutic strategies for these conditions.

References:

1. Wu, Hui-Yuan, Rong, Yongqi, Bansal, Parmil K, Guo, Hong, Morgan, James I. 2022. TTLL1 and TTLL4 polyglutamylases are required for the neurodegenerative phenotypes in pcd mice. In PLoS genetics, 18, e1010144. doi:10.1371/journal.pgen.1010144. https://pubmed.ncbi.nlm.nih.gov/35404950/

2. Ping, Yashuang, Ohata, Kenji, Kikushima, Kenji, Konishi, Yoshiyuki, Setou, Mitsutoshi. 2023. Tubulin Polyglutamylation by TTLL1 and TTLL7 Regulate Glutamate Concentration in the Mice Brain. In Biomolecules, 13, . doi:10.3390/biom13050784. https://pubmed.ncbi.nlm.nih.gov/37238654/

3. Northington, Kyle R, Calderon, Jasmynn, Bates, Emily A. 2024. Netrin-1 stimulated axon growth requires the polyglutamylase TTLL1. In Frontiers in neuroscience, 18, 1436312. doi:10.3389/fnins.2024.1436312. https://pubmed.ncbi.nlm.nih.gov/39469034/

4. Trichet, V, Ruault, M, Roizès, G, De Sario, A. . Characterization of the human tubulin tyrosine ligase-like 1 gene (TTLL1) mapping to 22q13.1. In Gene, 257, 109-17. doi:. https://pubmed.ncbi.nlm.nih.gov/11054573/

5. Jentzsch, Jana, Wunderlich, Hannes, Thein, Marinus, Weiss, Matthias, Ersfeld, Klaus. 2024. Microtubule polyglutamylation is an essential regulator of cytoskeletal integrity in Trypanosoma brucei. In Journal of cell science, 137, . doi:10.1242/jcs.261740. https://pubmed.ncbi.nlm.nih.gov/38205672/

6. Vogel, P, Hansen, G, Fontenot, G, Read, R. 2010. Tubulin tyrosine ligase-like 1 deficiency results in chronic rhinosinusitis and abnormal development of spermatid flagella in mice. In Veterinary pathology, 47, 703-12. doi:10.1177/0300985810363485. https://pubmed.ncbi.nlm.nih.gov/20442420/