Disruption of axonal transport in motor neuron diseases

Int J Mol Sci. 2012;13(1):1225-38. doi: 10.3390/ijms13011225. Epub 2012 Jan 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Axonal Transport / physiology*
  • Axons / metabolism
  • Dynactin Complex
  • Dyneins / chemistry
  • Dyneins / metabolism
  • Humans
  • Intermediate Filaments / metabolism
  • Kinesin / chemistry
  • Kinesin / metabolism
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Motor Neuron Disease / metabolism*
  • Motor Neuron Disease / pathology

Substances

  • DCTN1 protein, human
  • Dctn1 protein, mouse
  • Dynactin Complex
  • Microtubule-Associated Proteins
  • Dyneins
  • Kinesin