Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death

Hristelina S. Ilieva, Koji Yamanaka, Shelle Malkmus, Osamu Kakinohana, Tony Yaksh, Martin Marsala, Don W. Cleveland

Research output: Contribution to journalArticlepeer-review

Abstract

Dominant mutations in cytoplasmic dynein (Loa or Cra) have been reported to provoke selective, age-dependent killing of motor neurons, while paradoxically slowing degeneration and death of motor neurons in one mouse model of an inherited form of ALS. Examination of Loa animals reveals no degeneration of large caliber α-motor neurons beyond an age-dependent loss (initiating only after 18 months) that was comparable in Loa and wild-type littermates. Absence of Loa-mediated α-motor neuron loss contrasted with dramatic, sustained, mutant dynein-mediated postnatal loss of lumbar proprioceptive sensory axons, accompanied by decreased excitatory glutamatergic inputs to motor neurons. In mouse models of inherited ALS caused by mutations in superoxide dismutase (SOD1), mutant dynein modestly prolonged survival in the one mouse model with the most extensive motor neuron loss (SODG93A) while showing marginal (SODG85R) or no (SODG37R) benefit in models with higher numbers of surviving motor neurons at end stage. These findings support a noncell autonomous, excitotoxic contribution from proprioceptive sensory neurons that modestly accelerates disease onset in inherited ALS.

Original languageEnglish (US)
Pages (from-to)12599-12604
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number34
DOIs
StatePublished - Aug 26 2008

Keywords

  • Cytoplasmic dynein
  • Excitotoxicity
  • Noncell autonomous
  • Sensory neurons

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death'. Together they form a unique fingerprint.

Cite this