The dynactin p150 subunit: cell biology studies of sequence changes found in ALS/MND and Parkinsonian syndromes

J Neural Transm (Vienna). 2013 May;120(5):785-98. doi: 10.1007/s00702-012-0910-z. Epub 2012 Nov 11.

Abstract

The dynactin p150glued subunit, encoded by the gene DCTN1 is part of the dynein-dynactin motor protein complex responsible for retrograde axonal transport. This subunit is a candidate modifier for neurodegenerative diseases, in particular motoneuron and extrapyramidal diseases. Based on an extensive screening effort of all 32 exons in more than 2,500 ALS/MND patients, patients suffering from Parkinsonian Syndromes and controls, we investigated 24 sequence variants of p150 in cell-based studies. We used both non-neuronal cell lines and primary rodent spinal motoneurons and report on cell biological abnormalities in five of these sequence alterations and also briefly report on the clinical features. Our results suggest the presence of biological changes caused by some p150 mutants pointing to a potential pathogenetic significance as modifier of the phenotype of the human disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Autophagy-Related Proteins
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Chlorocebus aethiops
  • Dynactin Complex
  • Embryo, Mammalian
  • Female
  • Green Fluorescent Proteins / genetics
  • Humans
  • Male
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / metabolism
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Motor Neurons / ultrastructure
  • Mutation / genetics
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / pathology*
  • Pregnancy
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Retrospective Studies
  • Spinal Cord / cytology
  • Time Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Autophagy-Related Proteins
  • Carrier Proteins
  • Cell Cycle Proteins
  • DCTN1 protein, human
  • Dynactin Complex
  • Microtubule-Associated Proteins
  • UBQLN1 protein, human
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease