Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors

Kyoko Chiba, Hironori Takahashi, Min Chen, Hiroyuki Obinata, Shogo Arai, Koichi Hashimoto, Toshiyuki Oda, Richard Mckenney, Shinsuke Niwa

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)18429-18434
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number37
DOIs
StatePublished - Sep 10 2019

Keywords

  • Axonal transport
  • Hereditary spastic paraplegia
  • KIF1A
  • Kinesin
  • UNC-104

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors'. Together they form a unique fingerprint.

Cite this