KIF1A c.773C > T impairs neural progenitor differentiation and axonal transport in association with dysregulated Wnt/β-catenin-BDNF signaling.

Abstract

Pathogenic KIF1A variants are established cause neurodevelopmental and neurodegenerative disorders. However, the mechanisms by which they perturb early human neural development remains undefined. Here, we identified a heterozygous KIF1A c.773C > T (p.T258M) mutation in a Chinese family with hereditary spastic paraplegia and modeled its pathogenicity using patient-derived iPSCs and CRISPR-Cas9-corrected isogenic controls. We found that KIF1A-mutant neural stem cells (NSCs) exhibited hyperproliferation, impaired cell-cycle exit, and defective neuronal differentiation, accompanied by defective neurite outgrowth, neuronal complexity, and calcium activity. Mechanistically, the KIF1A c.773C > T mutation compromised the binding affinity of KIF1A for β-tubulin and thereby impaired microtubule-associated localization of BDNF and synaptophysin. Integrated transcriptomic and biochemical analyses further revealed dysregulation of the Wnt/β-catenin signaling pathway. Notably, pharmacological activation of Wnt signaling restored BDNF expression, whereas exogenous BDNF rescued the proliferative and differentiative defects, indicating a potential functional relationship between BDNF and Wnt/β-catenin signaling. Collectively, these findings suggested that dysregulated Wnt/β-catenin-BDNF signaling may serve as a contributory mechanism linking KIF1A motor dysfunction to aberrant neural stem cell fate.