Fisetin Rescues Pathogenic Mutation of Kinesin
Mutations in the kinesin KIF1A cause impaired axonal transport, resulting in neurological disorders or neurodevelopmental disorders known as KAND (KIF1A-associated neurological disorder). In clinical practice, there is limited knowledge regarding effective interventions and treatment methods for these mutations. The Caenorhabditis elegans serves as a valuable genetic model for studying KAND.
The research group of Prof. FENG Wei from Institute of Biophysics of the Chinese Academy of Sciences, and Prof. OU Guangshuo from Tsinghua University, observed the impact of the KIF1A (R11Q) mutation in patients with comorbid autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). They introduced the KIF1A (R11Q) variant into Caenorhabditis elegans homologous gene UNC-104, replicating the coordinated and locomotion impairments seen in KAND.
Structural analysis revealed that this mutation is located near the ATP-binding pocket of the KIF1A motor domain, and the mutant nematodes exhibited behavioral incoordination. Through genetic screening of the KIF1A (R11Q) mutant nematodes, 20 mutations were identified that could correct the behavioral defects caused by this mutation. In vitro experiments found that two of these mutations partially restored the motor activity of KIF1A.
Based on this finding, the researchers further investigated whether there might be a small molecule with a similar rescue effect. By screening dietary supplements known to improve neurological health, they discovered that a plant flavonol called Fisetin could improve the locomotion and morphology defects caused by the KIF1A (R11Q) mutation, without affecting the wild-type KIF1A.
This study, published in PNAS, provides new insights into the treatment of KAND. The intervention of the small molecule Fisetin helps enhance the activity of the pathogenic KIF1A variant, potentially improving symptoms associated with KAND-related diseases.
"Although our experiments showed that Fisetin did not show a significant effect on the motor kinetics of wild-type KIF1A in vitro and in vivo, we strongly recommend that medical professionals or specialists in the field of neurodevelopmental disorders be consulted before initiating any Fisetin supplementation for KAND patients," said the researchers.
Figure 1. Structural model of Fisetin docking into the ATP-binding pocket of the KIF1A(R11Q) mutant
Article link: https://doi.org/10.1073/pnas.2311936121
Contact: FENG Wei
Institute of Biophysics, Chinese Academy of Sciences
Beijing 100101, China
(Reported by Prof. FENG Wei's group)