Unique Function of Kinesin Kif5A in Localization of Mitochondria in Axons

• DOI: 10.1523/jneurosci.2770-14.2014
• Publication Date: 2014-10-29T17:07:51Z
• Authors: Philip D. Campbell; Kimberle Shen; Matthew R. Sapio; Thomas D. Glenn; William S. Talbot; Florence L. Marlow
• Keywords: 0303 health sciences; 03 medical and health sciences; Nerve Degeneration; Animals; Kinesins; Zebrafish Proteins; Axonal Transport; Axons; Zebrafish; Mitochondria

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 zebrafishkif5Aamutants exhibit hyperexcitability, peripheral polyneuropathy, and axonal degeneration reminiscent of CMT and HSP. Strikingly, althoughkif5genes are thought to act largely redundantly in other contexts, and zebrafish peripheral neurons express fivekif5genes,kif5Aamutant 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 thekinesin-3,kif1b, or its adaptorkbp, 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.