TTLL1 is the catalytic subunit of a neuronal tubulin polyglutamylase complex that catalyzes polyglutamylation—the addition of glutamate side chains to tubulin's C-terminal tail 1. Unlike autonomous polyglutamylases, TTLL1 requires association with other proteins for catalytic activity and likely mediates chain elongation rather than initiation, modifying both alpha- and beta-tubulins with preference for alpha-tubulin 1. This modification is essential for ciliary and flagellar biogenesis and motility; TTLL1-deficient mice develop primary ciliary dyskinesia-like phenotypes including chr22 rhinosinusitis and male infertility from defective sperm flagella 2. TTLL1 regulates respiratory cilia beating asymmetry and is required for normal male fertility 2. Beyond cilia/flagella, TTLL1 mediates KLF4 polyglutamylation, preventing its ubiquitination and sustaining stability during somatic cell reprogramming and embryogenesis 3. Brain polyglutamylation by TTLL1 and TTLL7 modulates glutamate homeostasis, suggesting a role in neurotransmitter metabolism 4. In disease contexts, loss of TTLL1 attenuates neurodegeneration in Purkinje cells, mitral cells, and retinal photoreceptors in Purkinje cell degeneration mice by reducing hyperglutamylation 5. Genomic associations link TTLL1 to Alzheimer's disease risk, potentially through cytoskeletal organization mechanisms 6.