Tubulin autoregulation mediator TTC5 regulates neuronal morphology and migration

04/11/2026

AI Summary

TTC5 mediates tubulin autoregulation in iPSC-derived cortical neurons; its loss disables autoregulation and reduces microtubule polymerisation.
Loss or mutation of TTC5 impairs axonal outgrowth and dendritic arborisation while increasing neuronal and non-neuronal motility.
TTC5 deficiency in mice disrupts neuronal arborisation and causes hypermigration; patient TTC5 mutants phenocopy motility defects, linking TTC5 to neurodevelopmental disease.

TL;DR (AI Generated)

Tetratricopeptide repeat domain 5 (TTC5) mediates tubulin autoregulation, the co-translational degradation of tubulin transcripts in response to excess soluble tubulin, and TTC5 mutations cause cerebral atrophy with speech and motor impairment.

Patient-derived TTC5 disease mutants phenocopy this motility dysregulation, directly linking loss of TTC5 function to neurological deficits seen in patients.

Together, these findings establish TTC5 as an essential regulator of neuronal morphogenesis and connectivity, with direct implications for TTC5-associated neurodevelopmental disease.

Basic summary

Curr Biol. 2026 Nov 3:S0960-9822(26)01362-X. doi: 10.1016/j.cub.2026.10.028. Online ahead of print.

ABSTRACT

Microtubule dynamics are essential for neuronal development, yet how neurons regulate tubulin levels remains poorly understood. Tetratricopeptide repeat domain 5 (TTC5) mediates tubulin autoregulation, the co-translational degradation of tubulin transcripts in response to excess soluble tubulin, and TTC5 mutations cause cerebral atrophy with speech and motor impairment. Here, we show that tubulin autoregulation is active in induced pluripotent stem cell (iPSC)-derived cortical neurons and depends on TTC5. TTC5 loss, or structure-guided mutations that disable autoregulation suppress microtubule polymerization, axonal outgrowth, and arborization, while enhancing cellular motility. Motility changes extend to non-neuronal cells, where they alter focal adhesion dynamics and can be rescued by manipulating soluble tubulin levels. Furthermore, downregulation of TTC5 interactor and autoregulation mediator S-phase cyclin A-associated protein in the endoplasmic reticulum (SCAPER) also suppresses neurite outgrowth and enhances motility. In vivo, TTC5 loss in mouse cortical projection neurons disrupts axon and dendrite arborization and causes hypermigration, recapitulating the cellular phenotypes observed in vitro. Patient-derived TTC5 disease mutants phenocopy this motility dysregulation, directly linking loss of TTC5 function to neurological deficits seen in patients. Together, these findings establish TTC5 as an essential regulator of neuronal morphogenesis and connectivity, with direct implications for TTC5-associated neurodevelopmental disease.

PMID:42976848 | DOI:10.1016/j.cub.2026.10.028

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