A plant flavonol and genetic suppressors rescue a pathogenic mutation associated with kinesin in neurons

• 成果类型: Article
• 署名作者: Chai, Yongping; Li, Dong; Gong, Weibin; Ke, Jingyi; Tian, Dianzhe; Chen, Zhe; Guo, Angel; Guo, Zhengyang; Li, Wei; Feng, Wei; Ou, Guangshuo
• 署名单位: Tsinghua University; Tsinghua University; Chinese Academy of Sciences; Institute of Biophysics, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Tsinghua University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15202
• DOI: 10.1073/pnas.2311936121
• 发表日期: 2024-01-30
• 关键词: de-novo mutations; axonal-transport; spastic paraplegia; vesicle transport; synaptic vesicles; monomeric motor; c-elegans; kif1a; mechanisms; unc-104

摘要

KIF1A, a microtubule- based motor protein responsible for axonal transport, is linked to a group of neurological disorders known as KIF1A- associated neurological disorder (KAND). Current therapeutic options for KAND are limited. Here, we introduced the clinically relevant KIF1A(R11Q) variant into the Caenorhabditis elegans homolog UNC- 104, resulting in uncoordinated animal behaviors. Through genetic suppressor screens, we identified intragenic mutations in UNC- 104's motor domain that rescued synaptic vesicle localization and coordinated movement. We showed that two suppressor mutations partially recovered motor activity in vitro by counteracting the structural defect caused by R11Q at KIF1A's nucleotide- binding pocket. We found that supplementation with fisetin, a plant flavonol, improved KIF1A(R11Q) worms' movement and morphology. Notably, our biochemical and single- molecule assays revealed that fisetin directly restored the ATPase activity and processive movement of human KIF1A(R11Q) without affecting wild- type KIF1A. These findings suggest fisetin as a potential intervention for enhancing KIF1A(R11Q) activity and alleviating associated defects in KAND.