UNC-45A drives ATP-independent microtubule severing via defect recognition and repair inhibition, contributing to neurite dystrophy

UNC-45A is the only known ATP-independent microtubule severing protein. Using in vitro reconstitution and TIRF microscopy, we show that, unlike canonical severing enzymes such as katanin, spastin, and fidgetin, which hydrolyze ATP to remove tubulin dimers and promote lattice repair, UNC-45A selectively binds to pre-existing microtubule defects and inhibits GTP-tubulin incorporation. This mechanism prevents the formation of stabilized hot spots that typically protect microtubules from disassembly, resulting in persistent lattice damage and net microtubule loss, even in the presence of physiological levels of free GTP-tubulin.

We further demonstrate that UNC-45A localizes near amyloid deposits in both mouse models and human cases of Alzheimer’s disease (AD). In cultured neurons, UNC-45A accumulates in axonal swellings—regions of pronounced microtubule disruption and experimental surrogates for dystrophic neurites in AD—and exacerbates their size and number, particularly under conditions mimicking microtubule damage. Notably, this is the first report of a microtubule severing protein that both localizes near amyloid plaques in tissue and accumulates in neurite swellings in cultured neurons, where it modulates their pathology.

Together, our findings establish the mechanism of ATP-independent, damage-responsive severing pathway that couple defects recognition to repair inhibition, defining a new paradigm in microtubule quality control with broad implications for cytoskeletal integrity and remodeling in health and disease.