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The Journal of Neuroscience, December 19, 2007, 27(51):13982-13990; doi:10.1523/JNEUROSCI.4226-07.2007

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Neurobiology of Disease
The G59S Mutation in p150^glued Causes Dysfunction of Dynactin in Mice

Chen Lai,^1 * Xian Lin,^1,2 * Jayanth Chandran,¹ Hoon Shim,¹ Wan-Jou Yang,¹ and Huaibin Cai¹

¹Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, and ²Department of Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510089, China

Correspondence should be addressed to Huaibin Cai, Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, MSC 3707, 35 Convent Drive, Bethesda, MD 20892-3707. Email: caih{at}mail.nih.gov

The G59S missense mutation at the conserved microtubule-binding domain of p150^glued, 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 p150^glued 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 p150^glued heterozygous knock-out mice. Our findings indicate that the G59S mutation in p150^glued abrogates the normal function of p150^glued and accelerates motor neuron degeneration.

Key words: dynactin; dynein; p150^glued; motor neuron disease; mouse model; ALS

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Received Sept. 14, 2007; revised Nov. 1, 2007; accepted Nov. 2, 2007.

Correspondence should be addressed to Huaibin Cai, Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, MSC 3707, 35 Convent Drive, Bethesda, MD 20892-3707. Email: caih{at}mail.nih.gov

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