A plant flavonol and genetic suppressors rescue a pathogenic mutation associated with kinesin in neurons.
Proc Natl Acad Sci U S A
; 121(5): e2311936121, 2024 Jan 30.
Article
in En
| MEDLINE
| ID: mdl-38271337
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Synaptic Vesicles
/
Kinesins
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2024
Type:
Article