title: Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death.
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 alpha-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 alpha-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 (SOD(G93A)) while showing marginal (SOD(G85R)) or no (SOD(G37R)) 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.
authors: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
authors: Hristelina S
authors: HS
authors: Ilieva
authors: Koji
authors: K
authors: Yamanaka
authors: Shelle
authors: S
authors: Malkmus
authors: Osamu
authors: O
authors: Kakinohana
authors: Tony
authors: T
authors: Yaksh
authors: Martin
authors: M
authors: Marsala
authors: Don W
authors: DW
authors: Cleveland
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000473:pathology*; D016923:Cell Death; D002470:Cell Survival; D004195:Disease Models, Animal; D004398:Dyneins / Q000235:genetics*; D051379:Mice; D009046:Motor Neurons / Q000473:pathology*; D009154:Mutation; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D004398:Dyneins