A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation

J Cell Biol. 2006 Feb 27;172(5):733-45. doi: 10.1083/jcb.200511068.

Abstract

The microtubule motor cytoplasmic dynein and its activator dynactin drive vesicular transport and mitotic spindle organization. Dynactin is ubiquitously expressed in eukaryotes, but a G59S mutation in the p150Glued subunit of dynactin results in the specific degeneration of motor neurons. This mutation in the conserved cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain lowers the affinity of p150Glued for microtubules and EB1. Cell lines from patients are morphologically normal but show delayed recovery after nocodazole treatment, consistent with a subtle disruption of dynein/dynactin function. The G59S mutation disrupts the folding of the CAP-Gly domain, resulting in aggregation of the p150Glued protein both in vitro and in vivo, which is accompanied by an increase in cell death in a motor neuron cell line. Overexpression of the chaperone Hsp70 inhibits aggregate formation and prevents cell death. These data support a model in which a point mutation in p150Glued causes both loss of dynein/dynactin function and gain of toxic function, which together lead to motor neuron cell death.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • COS Cells
  • Cells, Cultured
  • Chlorocebus aethiops
  • Dynactin Complex
  • Dyneins / metabolism
  • HSP70 Heat-Shock Proteins / biosynthesis
  • HSP70 Heat-Shock Proteins / genetics
  • Heredodegenerative Disorders, Nervous System / genetics*
  • Heredodegenerative Disorders, Nervous System / metabolism*
  • Humans
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / physiology*
  • Microtubules / chemistry
  • Microtubules / genetics
  • Microtubules / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Motor Neurons / metabolism*
  • Point Mutation

Substances

  • Dynactin Complex
  • HSP70 Heat-Shock Proteins
  • MAPRE1 protein, human
  • Microtubule-Associated Proteins
  • Dyneins