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.
Highlights
Motor neurons are highly specialized cells that possess the longest axons, which connect the soma with synaptic sites distant from the cell body
Several studies identified mutations in microtubule-based motor proteins of the kinesin and dynein superfamilies in certain hereditary forms of motor neuron diseases (MNDs): mutations in the genes encoding kinesin 1 motors (KIF5A) in certain types of hereditary spastic paraplegias (HSPs) [6]; two missense mutations in the dynein gene in the Legs at odd angles (Loa) and Cra mouse models of amyotrophic lateral sclerosis (ALS) [7]; and a mutation in the dynactin-1 gene linked to a familial form of lower motor neuron disease [8]
Neurofilaments are transported along microtubules by kinesin and the dynein/dynactin-1 complex, and dysfunctions of these motor proteins lead to accumulation of neurofilaments in axons and somata, as observed in the KIF5A mutant mouse and dynactin-1 mutant mouse [20,30,33,34]
Summary
Motor neurons are highly specialized cells that possess the longest axons (more than 1 m long in human), which connect the soma with synaptic sites distant from the cell body. Axons can represent >99% of the volume of a cell, protein and lipid syntheses occur almost exclusively in the cell body [1]. An increasing number of reports link defects in axonal transport with motor neuron degenerations, such as amyotrophic lateral sclerosis (ALS), spinal and bulbar muscular atrophy (SBMA), spinal muscular atrophy (SMA), and hereditary spastic paraplegias (HSPs) [1,5].
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