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. 2005 May 23;169(4):561-7.
doi: 10.1083/jcb.200501085.

A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice

Dairin Kieran  1 , Majid Hafezparast, Stephanie Bohnert, James R T Dick, Joanne Martin, Giampietro Schiavo, Elizabeth M C Fisher, Linda Greensmith
Affiliations

A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice

Dairin Kieran et al. J Cell Biol. .

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by motoneuron degeneration and muscle paralysis. Although the precise pathogenesis of ALS remains unclear, mutations in Cu/Zn superoxide dismutase (SOD1) account for approximately 20-25% of familial ALS cases, and transgenic mice overexpressing human mutant SOD1 develop an ALS-like phenotype. Evidence suggests that defects in axonal transport play an important role in neurodegeneration. In Legs at odd angles (Loa) mice, mutations in the motor protein dynein are associated with axonal transport defects and motoneuron degeneration. Here, we show that retrograde axonal transport defects are already present in motoneurons of SOD1(G93A) mice during embryonic development. Surprisingly, crossing SOD1(G93A) mice with Loa/+ mice delays disease progression and significantly increases life span in Loa/SOD1(G93A) mice. Moreover, there is a complete recovery in axonal transport deficits in motoneurons of these mice, which may be responsible for the amelioration of disease. We propose that impaired axonal transport is a prime cause of neuronal death in neurodegenerative disorders such as ALS.

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Figures

Figure 1.
Figure 1.
Life span, weight loss, and expression of human SOD1 transgene. The graphs show (a) the increase in life span and (b) delayed loss of body weight in the Loa/SOD1G93A mice (n = 18–20). Examples of spinal cord sections from SOD1G93A and Loa/SOD1G93A mice (c and d, respectively) immunostained for human SOD1 (bar = 70 μm). (e) A representative Western blot of human SOD1 using brain tissue.
Figure 2.
Figure 2.
Muscle force and phenotype. (a) Maximum force generated by EDL muscles (n = 10–12) in each group at 120 d of age (g = grams). Error bars = SEM. Fatigue traces from EDL muscles of (b) WT, (c) Loa/+, (d) SOD1G93A, and (e) Loa/SOD1G93A mice at 120 d of age (bar = 30 s).
Figure 3.
Figure 3.
Motor unit survival. Examples of motor unit traces from EDL muscles (n = 10) in (a) WT, (b) Loa/+, (c) SOD1G93A, and (d) Loa/SOD1G93A mice. (e) Mean motor unit survival in each group at 120 d of age. Error bars = SEM.
Figure 4.
Figure 4.
Motoneuron survival. Cross sections of spinal cord showing motoneurons in the sciatic motor pools (dotted areas, magnified in insets) from (a) WT, (b) Loa/+, (c) SOD1G93A, and (d) Loa/SOD1G93A littermates at 120 d of age (n = 8). Bar: 400 μm (main panels), 200 μm (insets). (e) Mean motoneuron survival at 120 d of age. Error bars = SEM.
Figure 5.
Figure 5.
Kinetic analysis of retrograde axonal transport. The kymographs show the traces of TeNT HC–positive compartments in motoneuron axons from WT, Loa/+, SOD1G93A, and Loa/SOD1G93A primary cultures (a). The width of kymographs corresponds to 65 μm of axon length. The relative abundance of stationary and oscillating TeNT HC carriers is not related to their genotype. Arrows show paused carriers; arrowheads show anterograde phases. See also Videos 3–6 (available at http://www.jcb.org/cgi/content/full/jcb.200501085/DC1). (b) Displacement of TeNT HC–positive compartments shown in panel a. The start of tracking for each carrier was set to time = 0. (c) Speed distribution of the TeNT HC–positive carriers in motoneurons from WT, Loa/+, SOD1G93A, and Loa/SOD1G93A E13 embryos. Single movements of TeNT HC–488 carriers, which are described by their progress between two consecutive frames, have been plotted against their frequency. Retrograde transport is conventionally shown as positive, anterograde as negative, and pauses during movement are grouped at 0 μm/s. Error bars = SEM.
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References

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