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

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 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.

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

“…We performed functional assays in which motors were expressed in their native cellular environment, which can provide insights that cannot be gleaned from in vitro experiments (see, e.g., Chai et al, 2024 ). However, further data from in vitro experiments, which can determine important motor parameters such as run length and velocity, would allow more informed conclusions to be drawn from our data.…”