Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases

Neuron. 2017 Oct 11;96(2):285-297. doi: 10.1016/j.neuron.2017.07.029.


Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by degeneration of upper and lower motor neurons in the brain and spinal cord. The hallmark pathological feature in most cases of ALS is nuclear depletion and cytoplasmic accumulation of the protein TDP-43 in degenerating neurons. Consistent with this pattern of intracellular protein redistribution, impaired nucleocytoplasmic trafficking has emerged as a mechanism contributing to ALS pathology. Dysfunction in nucleocytoplasmic transport is also an emerging theme in physiological aging and other related neurodegenerative diseases, such as Huntington's and Alzheimer's diseases. Here we review transport through the nuclear pore complex, pointing out vulnerabilities that may underlie ALS and potentially contribute to this and other age-related neurodegenerative diseases.

Keywords: ALS; C9ORF72; FTD; aging; dipeptide repeats; neurodegenerative diseases; nuclear pore; nucleocytoplasmic transport.

Publication types

  • Review

MeSH terms

  • Active Transport, Cell Nucleus / physiology*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • C9orf72 Protein
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Mutation / genetics
  • Neurodegenerative Diseases / genetics
  • Protein Transport / physiology
  • Proteins / genetics
  • Proteins / metabolism


  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • Proteins
  • TARDBP protein, human