Posted - December 2019 in Research Highlights
Increased, not decreased, activity found
More than 10 mutations in the KIF1A gene are associated with SPG30 type HSP. It was previously thought that a loss-of-function mechanism inhibiting this gene’s job in axonal transport was the cause, but this had been observed not to be the case in some of these mutations.
This study of earthworms with KIF1A mutations showed that hyper activation of motility led to increased axonal transport to the tips of the axons where abnormal accumulation of transport products occurred.
KIF1A is a kinesin family motor involved in the axonal transport of synaptic vesicle precursors (SVPs) along microtubules (MTs). In humans, more than 10 point mutations in KIF1A are associated with the motor neuron disease hereditary spastic paraplegia (SPG). However, not all of these mutations appear to inhibit the motility of the KIF1A motor, and thus a cogent molecular explanation for how KIF1A mutations lead to neuropathy is not available.
In this study, we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility. Introduction of the corresponding mutations into the Caenorhabditis elegans KIF1A homolog unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs.
Our data reveal that hyperactivation of kinesin motor activity, rather than its loss of function, is a cause of motor neuron disease in humans.
SOURCE: Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18429-18434. doi: 10.1073/pnas.1905690116. Epub 2019 Aug 27. PMID: 31455732
Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.
1 Department of Molecular and Cellular Biology, University of California, Davis, CA 95616.
2 Department of Anatomy and Structural Biology, Graduate School of Medicine, University of Yamanashi, Chuo, 409-3898 Yamanashi, Japan.
3 Department of System Information Sciences, Graduate School of Information Sciences, Tohoku University, Sendai, 980-8579 Miyagi, Japan.
4 Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, 980-0845 Miyagi, Japan.
5 Department of Robotics, Graduate School of Engineering, Tohoku University, Sendai, 980-8579 Miyagi, Japan.