Authors
Yong Liu, Jiayuan Wang, Ruonan Duan, Xiaoyi Wang, Jie Zhang, Mengru Li, Jian Sun, Yulin Zeng, Haopeng Kan, Tonghui Meng, Xinrui Liu, Yu Zhang, Jiexin Tang, Kexin Shi, Ziyu Wei, Yecheng Jin, Jiangxia Li, Xi Li, Qiji Liu, Jinlong Ma, Yuan Gao, Wenjie Sun
Published in
Neurobiology of disease. Pages 107645. Oct 11, 2026. Epub Oct 11, 2026.
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.
PMID:
42860237
Bibliographic data and abstract were imported from PubMed on 12 Oct 2026.
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