UNC-45A Drives ATP-Independent Microtubule Destabilization 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 microtubule 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 surrogates for dystrophic neurites in AD, and exacerbated 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 a novel ATP-independent, damage-responsive severing pathway that couple defect recognition to repair inhibition, defining a new paradigm in microtubule quality control with broad implications for the cytoskeletal integrity and remodeling in health and disease