Unique function of Kinesin Kif5A in localization of mitochondria in axons

Philip D. Campbell, Kimberle Shen, Matthew R. Sapio, Thomas D. Glenn, William S. Talbot, Florence L. Marlow

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Mutations in Kinesin proteins (Kifs) are linked to various neurological diseases, but the specific and redundant functions of the vertebrate Kifs are incompletely understood. For example, Kif5A, but not other Kinesin-1 heavy-chain family members, is implicated in Charcot-Marie-Tooth disease (CMT) and Hereditary Spastic Paraplegia (HSP), but the mechanism of its involvement in the progressive axonal degeneration characteristic of these diseases is not well understood. We report that zebrafish kif5Aa mutants exhibit hyperexcitability, peripheral polyneuropathy, and axonal degeneration reminiscent of CMT and HSP. Strikingly, although kif5 genes are thought to act largely redundantly in other contexts, and zebrafish peripheral neurons express five kif5 genes, kif5Aa mutant peripheral sensory axons lack mitochondria and degenerate. We show that this Kif5Aa-specific function is cell autonomous and is mediated by its C-terminal tail, as only Kif5Aa and chimeric motors containing the Kif5Aa C-tail can rescue deficits. Finally, concurrent loss of the kinesin-3, kif1b, or its adaptor kbp, exacerbates axonal degeneration via a nonmitochondrial cargo common to Kif5Aa. Our results shed light on Kinesin complexity and reveal determinants of specific Kif5A functions in mitochondrial transport, adaptor binding, and axonal maintenance.

Original languageEnglish (US)
Pages (from-to)14717-14732
Number of pages16
JournalJournal of Neuroscience
Volume34
Issue number44
DOIs
StatePublished - Oct 29 2014

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Keywords

  • Axon degeneration
  • CMT
  • HSP
  • Kinesin
  • Mitochondria
  • Sensory neuron

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Campbell, P. D., Shen, K., Sapio, M. R., Glenn, T. D., Talbot, W. S., & Marlow, F. L. (2014). Unique function of Kinesin Kif5A in localization of mitochondria in axons. Journal of Neuroscience, 34(44), 14717-14732. https://doi.org/10.1523/JNEUROSCI.2770-14.2014