The G59S mutation in p150glued causes dysfunction of dynactin in mice

Chen Lai, Xian Lin, Jayanth Chandran, Hoon Shim, Wan Jou Yang, Huaibin Cai

    Research output: Contribution to journalArticlepeer-review

    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 p150glued G59S knock-in mice. We found that the G59S mutation destabilizes p150 glued and 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 p150glued heterozygous knock-out mice. Our findings indicate that the G59S mutation in p150glued abrogates the normal function of p150glued and accelerates motor neuron degeneration.

    Original languageEnglish (US)
    Pages (from-to)13982-13990
    Number of pages9
    JournalJournal of Neuroscience
    Volume27
    Issue number51
    DOIs
    StatePublished - Dec 19 2007

    Keywords

    • ALS
    • Dynactin
    • Dynein
    • Motor neuron disease
    • Mouse model
    • p150

    ASJC Scopus subject areas

    • Neuroscience(all)

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