Sensory axons lack mitochondria and degenerate
Mutations in Kinesin proteins lead to progressive axonal degeneration found in both Charcot-Marie-Tooth disease (CMT) and Hereditary Spastic Paraplegia (HSP). Affected sensory axons were found to lack mitochondria and degenerate.
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 non-mitochondrial 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.
SOURCE: J Neurosci. 2014 Oct 29;34(44):14717-32. doi: 10.1523/JNEUROSCI.2770-14.2014. Copyright © 2014 the authors 0270-6474/14/3414717-16$15.00/0. PMID: 25355224 [PubMed – in process] PMCID: PMC4212069 [Available on 2015/4/29]
Unique Function of Kinesin Kif5A in Localization of Mitochondria in Axons.
1 Departments of Developmental and Molecular Biology, and.
2 Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305.
3 Neuroscience, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, and.
4 Departments of Developmental and Molecular Biology, and Neuroscience, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, and [email protected].