Axonal transport deficit in a KIF5A –/– mouse model
Open Access
- 1 April 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in neurogenetics
- Vol. 13 (2), 169-179
- https://doi.org/10.1007/s10048-012-0324-y
Abstract
Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder preferentially affecting the longest corticospinal axons. More than 40 HSP genetic loci have been identified, among them SPG10, an autosomal dominant HSP caused by point mutations in the neuronal kinesin heavy chain protein KIF5A. Constitutive KIF5A knockout (KIF5A –/–) mice die early after birth. In these mice, lungs were unexpanded, and cell bodies of lower motor neurons in the spinal cord swollen, but the pathomechanism remained unclear. To gain insights into the pathophysiology, we characterized survival, outgrowth, and function in primary motor and sensory neuron cultures from KIF5A –/– mice. Absence of KIF5A reduced survival in motor neurons, but not in sensory neurons. Outgrowth of axons and dendrites was remarkably diminished in KIF5A –/– motor neurons. The number of axonal branches was reduced, whereas the number of dendrites was not altered. In KIF5A –/– sensory neurons, neurite outgrowth was decreased but the number of neurites remained unchanged. In motor neurons maximum and average velocity of mitochondrial transport was reduced both in anterograde and retrograde direction. Our results point out a role of KIF5A in process outgrowth and axonal transport of mitochondria, affecting motor neurons more severely than sensory neurons. This gives pathophysiological insights into KIF5A associated HSP, and matches the clinical findings of predominant degeneration of the longest axons of the corticospinal tract.This publication has 48 references indexed in Scilit:
- Kinesin-1/Hsc70-dependent mechanism of slow axonal transport and its relation to fast axonal transportThe EMBO Journal, 2010
- mNUDC is required for plus-end-directed transport of cytoplasmic dynein and dynactins by kinesin-1The EMBO Journal, 2009
- Tight Functional Coupling of Kinesin-1A and Dynein Motors in the Bidirectional Transport of NeurofilamentsMolecular Biology of the Cell, 2009
- Kinesin superfamily motor proteins and intracellular transportNature Reviews Molecular Cell Biology, 2009
- Consequences of Motor Copy Number on the Intracellular Transport of Kinesin-1-Driven Lipid DropletsCell, 2008
- LIS1 and NDEL1 coordinate the plus-end-directed transport of cytoplasmic dyneinThe EMBO Journal, 2008
- Intracellular Transport and Kinesin Superfamily Proteins, KIFs: Structure, Function, and DynamicsPhysiological Reviews, 2008
- Conventional Kinesin Holoenzymes Are Composed of Heavy and Light Chain HomodimersBiochemistry, 2008
- Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independentThe Journal of cell biology, 2006
- Building Complexity: An In Vitro Study of Cytoplasmic Dynein with In Vivo ImplicationsCurrent Biology, 2005