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Published 27 February 2006. doi:10.1083/jcb.200511068
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 172, Number 5, 733-745
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Article

 A motor neuron disease–associated mutation in p150Glued perturbs dynactin function and induces protein aggregation

Jennifer R. Levy1, Charlotte J. Sumner2, Juliane P. Caviston1, Mariko K. Tokito1, Srikanth Ranganathan2, Lee A. Ligon1, Karen E. Wallace1, Bernadette H. LaMonte1, George G. Harmison2, Imke Puls2, Kenneth H. Fischbeck2, and Erika L.F. Holzbaur1

1 Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
2 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Correspondence to Erika L.F. Holzbaur: holzbaur{at}mail.med.upenn.edu

The microtubule motor cytoplasmic dynein and its activator dynactin drive vesicular transport and mitotic spindle organization. Dynactin is ubiquitously expressed in eukaryotes, but a G59S mutation in the p150Glued subunit of dynactin results in the specific degeneration of motor neurons. This mutation in the conserved cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain lowers the affinity of p150Glued for microtubules and EB1. Cell lines from patients are morphologically normal but show delayed recovery after nocodazole treatment, consistent with a subtle disruption of dynein/dynactin function. The G59S mutation disrupts the folding of the CAP-Gly domain, resulting in aggregation of the p150Glued protein both in vitro and in vivo, which is accompanied by an increase in cell death in a motor neuron cell line. Overexpression of the chaperone Hsp70 inhibits aggregate formation and prevents cell death. These data support a model in which a point mutation in p150Glued causes both loss of dynein/dynactin function and gain of toxic function, which together lead to motor neuron cell death.

J.R. Levy and C.J. Sumner contributed equally to this paper.

Abbreviations used in this paper: CAP-Gly, cytoskeleton-associated protein, glycine-rich; DIC, dynein intermediate chain; PI, propidium iodide; SOD1, superoxide dismutase.


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