Unique Function of Kinesin Kif5A in Localization of Mitochondria in Axons

Journal of Neuroscience - Tập 34 Số 44 - Trang 14717-14732 - 2014
Philip D. Campbell1, Kimberle Shen2, Matthew R. Sapio3, Thomas D. Glenn2, William S. Talbot2, Florence L. Marlow1,3
11Departments of Developmental and Molecular Biology, and
23Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305
32Neuroscience, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, and

Tóm tắt

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.

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Journal of Neuroscience

Tập 34 Số 44

14717-14732

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