Axonal transport deficit in a KIF5A( -/- ) mouse model - PubMed (original) (raw)

Axonal transport deficit in a KIF5A( -/- ) mouse model

Kathrin N Karle et al. Neurogenetics. 2012 May.

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.

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Figures

Fig. 1

Fig. 1

Survival of primary motor and sensory neurons from KIF5A +/+, KIF5A +/–, and KIF5A –/– mice. The number of initially counted cells was set 100 % (day 0). The percentage of surviving cells was calculated for every day in culture. Motor neurons are indicated in continuous lines, sensory neurons in broken lines. Squares show KIF5A +/+, triangles KIF5A +/–, and circles KIF5A –/– mice. After 4 days in culture mean survival of KIF5A –/– motor neurons had declined to 43 ± 6 %, whereas in KIF5A +/– 76 ± 5 %, and in KIF5A +/+ mice 84 ± 6 % of the cells survived. In sensory neurons, there was no significant difference between the three genotypes at any time point. In total, at least 11 mice were analyzed per genotype. Mean and SEM are given. * denotes significant difference with p < 0.05 between KIF5A +/+ and KIF5A –/– motor neurons, ** significant difference with p < 0.05 between KIF5A +/+ and KIF5A –/–, and KIF5A +/– and KIF5A –/– motor neurons

Fig. 2

Fig. 2

Morphology of KIF5A +/+ and KIF5A –/– motor neurons. Motor neurons were stained with an antibody against neurofilament L (white). a Shows examples with axonal swellings (arrows, magnification box), b without axonal swellings. Bar 20 μm. Bar in the magnification box 10 μm

Fig. 3

Fig. 3

Axon and dendrite outgrowth of KIF5A +/+, KIF5A +/–, and KIF5A –/– motor neurons. Total axon length including all branches (continuous lines) and total dendrite length (broken lines) were measured after 2 and 4 days in vitro. Squares show KIF5A +/+, triangles KIF5A +/–, and circles KIF5A –/– motor neurons. Results are given as mean; due to clarity standard deviation indicators have been omitted. Measured values were linearly interpolated. For each genotype more than 150 cells from three independent experiments were analyzed

Fig. 4

Fig. 4

Process outgrowth of motor and sensory neurons from KIF5A +/+, KIF5A +/–, and KIF5A –/– mice. For each genotype more than 150 cells from three independent experiments were analyzed. Results are given as mean and standard deviation. Total axon length including all branches (a), total dendrite length (b), number of axonal branches (c), number of dendrites (d), and cell body area (e) are given for KIF5A +/+, KIF5A +/–, and KIF5A –/– motor neurons. Neurite outgrowth (f), number of neurites (g), and cell body area (h) in KIF5A +/+, KIF5A +/–, and KIF5A –/– sensory neurons. *p < 0.05, ***p < 0.001

Fig. 5

Fig. 5

Axonal transport of mitochondria in motor neurons. Maximum and average velocity of mitochondrial transport in anterograde (a and b) and retrograde (c and d) direction in KIF5A +/+, KIF5A +/–, and KIF5A –/– motor neurons. Mean and standard deviation are given. *p < 0.02, ***denotes p < 0.001. Results from ten independent experiments were summarized

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