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Status |
Public on Jan 08, 2024 |
Title |
A Plant Flavonol and Genetic Suppressors Rescue a Pathogenic Mutation Associated with Kinesin in Neurons |
Organism |
Caenorhabditis elegans |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
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 C. 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.
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Overall design |
To examine the unc-104 mRNA expression in the R9Q mutant and/or with the genetic suppressor presence, with the WT animal unc-104 mRNA levels.
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Contributor(s) |
Chai Y, Ke J, Ou G |
Citation(s) |
38271337 |
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Submission date |
Jan 07, 2024 |
Last update date |
Apr 08, 2024 |
Contact name |
Yongping Chai |
Organization name |
Tsinghua University 清华大学
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Street address |
Tsinghua University
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City |
Beijing |
State/province |
Beijing |
ZIP/Postal code |
100080 |
Country |
China |
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Platforms (1) |
GPL18730 |
Illumina HiSeq 1500 (Caenorhabditis elegans) |
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Samples (10)
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Relations |
BioProject |
PRJNA1062063 |
Supplementary file |
Size |
Download |
File type/resource |
GSE252693_RAW.tar |
1.7 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
Raw data are available in SRA |
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