Disruption of axonal transport in motor neuron diseases

Abstract

Motor neurons typically have very long axons, and fine-tuning axonal transport is crucial for their survival. The obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative motor neuron diseases. Depletions in dynein and dynactin-1, motor molecules regulating axonal trafficking, disrupt axonal transport in flies, and mutations in their genes cause motor neuron degeneration in humans and rodents. Axonal transport defects are among the early molecular events leading to neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS). Gene expression profiles indicate that dynactin-1 mRNA is downregulated in degenerating spinal motor neurons of autopsied patients with sporadic ALS. Dynactin-1 mRNA is also reduced in the affected neurons of a mouse model of spinal and bulbar muscular atrophy, a motor neuron disease caused by triplet CAG repeat expansion in the gene encoding the androgen receptor. Pathogenic androgen receptor proteins also inhibit kinesin-1 microtubule-binding activity and disrupt anterograde axonal transport by activating c-Jun N-terminal kinase. Disruption of axonal transport also underlies the pathogenesis of spinal muscular atrophy and hereditary spastic paraplegias. These observations suggest that the impairment of axonal transport is a key event in the pathological processes of motor neuron degeneration and an important target of therapy development for motor neuron diseases.

Keywords: amyotrophic lateral sclerosis; axonal transport; dynactin-1; dynein; hereditary spastic paraplegia; kinesin; motor neuron; neurofilament; spinal and bulbar muscular atrophy; spinal muscular atrophy.

Figure 1

Dysregulation of dynactin-1 in amyotrophic lateral sclerosis (ALS). (a) In situ hybridization of antisense (AS) and sense (S) dynactin-1 probes in spinal motor neurons of control and ALS subjects; (b) Relationship between the number of residual motor neurons and the percentage of neurons with decreased dynactin-1 (Reproduced from Jiang et al. [72]).

Figure 2

Disrupted retrograde axonal transport in a mouse model of spinal and bulbar muscular atrophy (SBMA). (a) Immunofluorescent anti-α-bungarotoxin (green) and anti-phospho NF-H (red) antibody staining of mouse skeletal muscle. Phosphorylated NF-H accumulates in the distal end of motor axons in the SBMA mice (AR-97Q); (b) Retrograde labeling of lumbar motor neurons by Fluoro-gold injection into the gastrocnemius muscle demonstrated decreased retrograde axonal transport in AR-97Q mice; (c) Immunohistochemistry shows decreased expression of dynactin-1 in motor neurons of spinal cord and brainstem of AR-97Q mice compared with wildtype mice. Accumulation of pathogenic AR is detected by 1C2, an anti-polyglutamine antibody (Reproduced from Katsuno et al. [62]).