A Plant Flavonol and Genetic Suppressors Rescue a Pathogenic Mutation Associated with Kinesin in Neurons

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2024 Jan 25

PMID 38271337

Authors

Yongping Chai

Dong Li

Weibin Gong

Jingyi Ke

Dianzhe Tian

Zhe Chen

Angel Guo

Zhengyang Guo

Wei Li

Wei Feng

Guangshuo Ou

Affiliations

Soon will be listed here.

Abstract

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 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.

Citing Articles

Characterization of the disease-causing mechanism of KIF3B mutations from ciliopathy patients.

Adams J, Sawe C, Rogers S, Reid J, Dasari R, Engelke M Front Mol Biosci. 2024; 11:1327963.

PMID: 38665936 PMC: 11043552. DOI: 10.3389/fmolb.2024.1327963.

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

Chai Y, Li D, Gong W, Ke J, Tian D, Chen Z Proc Natl Acad Sci U S A. 2024; 121(5):e2311936121.

PMID: 38271337 PMC: 10835061. DOI: 10.1073/pnas.2311936121.

References

Otsuka A, Jeyaprakash A, Garcia-Anoveros J, Tang L, Fisk G, Hartshorne T . The C. elegans unc-104 gene encodes a putative kinesin heavy chain-like protein. Neuron. 1991; 6(1):113-22. DOI: 10.1016/0896-6273(91)90126-k. View

Sleigh J, Rossor A, Fellows A, Tosolini A, Schiavo G . Axonal transport and neurological disease. Nat Rev Neurol. 2019; 15(12):691-703. DOI: 10.1038/s41582-019-0257-2. View

Boyle L, Rao L, Kaur S, Fan X, Mebane C, Hamm L . Genotype and defects in microtubule-based motility correlate with clinical severity in -associated neurological disorder. HGG Adv. 2021; 2(2). PMC: 8054982. DOI: 10.1016/j.xhgg.2021.100026. View

Klebe S, Lossos A, Azzedine H, Mundwiller E, Sheffer R, Gaussen M . KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations. Eur J Hum Genet. 2012; 20(6):645-9. PMC: 3355258. DOI: 10.1038/ejhg.2011.261. View

Cason S, Holzbaur E . Selective motor activation in organelle transport along axons. Nat Rev Mol Cell Biol. 2022; 23(11):699-714. DOI: 10.1038/s41580-022-00491-w. View

Kumari D, Ray K . Phosphoregulation of Kinesins Involved in Long-Range Intracellular Transport. Front Cell Dev Biol. 2022; 10:873164. PMC: 9203973. DOI: 10.3389/fcell.2022.873164. View

Citterio A, Arnoldi A, Panzeri E, Merlini L, DAngelo M, Musumeci O . Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. J Neurol. 2015; 262(12):2684-90. DOI: 10.1007/s00415-015-7899-9. View

Klopfenstein D, Vale R . The lipid binding pleckstrin homology domain in UNC-104 kinesin is necessary for synaptic vesicle transport in Caenorhabditis elegans. Mol Biol Cell. 2004; 15(8):3729-39. PMC: 491832. DOI: 10.1091/mbc.e04-04-0326. View

Chai Y, Li D, Gong W, Ke J, Tian D, Chen Z . A plant flavonol and genetic suppressors rescue a pathogenic mutation associated with kinesin in neurons. Proc Natl Acad Sci U S A. 2024; 121(5):e2311936121. PMC: 10835061. DOI: 10.1073/pnas.2311936121. View

10.

Byrd D, Kawasaki M, Walcoff M, HISAMOTO N, Matsumoto K, Jin Y . UNC-16, a JNK-signaling scaffold protein, regulates vesicle transport in C. elegans. Neuron. 2001; 32(5):787-800. DOI: 10.1016/s0896-6273(01)00532-3. View

11.

Langlois S, Tarailo-Graovac M, Sayson B, Drogemoller B, Swenerton A, Ross C . De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome. Eur J Hum Genet. 2015; 24(6):949-53. PMC: 4867456. DOI: 10.1038/ejhg.2015.217. View

12.

Kampkotter A, Gombitang Nkwonkam C, Zurawski R, Timpel C, Chovolou Y, Watjen W . Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Arch Toxicol. 2007; 81(12):849-58. DOI: 10.1007/s00204-007-0215-4. View

13.

Nitta R, Kikkawa M, Okada Y, Hirokawa N . KIF1A alternately uses two loops to bind microtubules. Science. 2004; 305(5684):678-83. DOI: 10.1126/science.1096621. View

14.

Maeder C, San-Miguel A, Wu E, Lu H, Shen K . In vivo neuron-wide analysis of synaptic vesicle precursor trafficking. Traffic. 2013; 15(3):273-91. DOI: 10.1111/tra.12142. View

15.

Byrd D, Pearlman J, Jin Y . Intragenic suppressors of ( ) identify potential roles of the conserved stalk region. MicroPubl Biol. 2022; 2022. PMC: 9005198. DOI: 10.17912/micropub.biology.000539. View

16.

Coulondre C, Miller J . Genetic studies of the lac repressor. III. Additional correlation of mutational sites with specific amino acid residues. J Mol Biol. 1977; 117(3):525-67. DOI: 10.1016/0022-2836(77)90056-0. View

17.

Hirokawa N, Kobayashi N, Pfister K, Bloom G, Brady S . Kinesin associates with anterogradely transported membranous organelles in vivo. J Cell Biol. 1991; 114(2):295-302. PMC: 2289077. DOI: 10.1083/jcb.114.2.295. View

18.

Taylor S, Santpere G, Weinreb A, Barrett A, Reilly M, Xu C . Molecular topography of an entire nervous system. Cell. 2021; 184(16):4329-4347.e23. PMC: 8710130. DOI: 10.1016/j.cell.2021.06.023. View

19.

Zhu Z, Chai Y, Jiang Y, Li W, Hu H, Li W . Functional Coordination of WAVE and WASP in C. elegans Neuroblast Migration. Dev Cell. 2016; 39(2):224-238. DOI: 10.1016/j.devcel.2016.09.029. View

20.

Hirokawa N, Nitta R, Okada Y . The mechanisms of kinesin motor motility: lessons from the monomeric motor KIF1A. Nat Rev Mol Cell Biol. 2009; 10(12):877-84. DOI: 10.1038/nrm2807. View