The G59S Mutation in p150gluedCauses Dysfunction of Dynactin in Mice
Open Access
- 19 December 2007
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 27 (51), 13982-13990
- https://doi.org/10.1523/jneurosci.4226-07.2007
Abstract
The G59S missense mutation at the conserved microtubule-binding domain of p150glued, a major component of dynein/dynactin complex, has been linked to an autosomal dominant form of motor neuron disease (MND). To study how this mutation affects the function of the dynein/dynactin complex and contributes to motor neuron degeneration, we generated p150gluedG59S knock-in mice. We found that the G59S mutation destabilizes p150gluedand disrupts the function of dynein/dynactin complex, resulting in early embryonic lethality of homozygous knock-in mice. Heterozygous knock-in mice, which developed normally, displayed MND-like phenotypes after 10 months of age, including excessive accumulation of cytoskeletal and synaptic vesicle proteins at neuromuscular junctions, loss of spinal motor neurons, increase of reactive astrogliosis, and shortening of gait compared with wild-type littermates and age-matched p150gluedheterozygous knock-out mice. Our findings indicate that the G59S mutation in p150gluedabrogates the normal function of p150gluedand accelerates motor neuron degeneration.Keywords
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