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

The Journal of Cell Biology
Jennifer R LevyErika L F Holzbaur

Abstract

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.

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
transfection
Affinity chromatography
fluorescence microscopy
density gradient centrifugation
immunoprecipitation
coimmunoprecipitation
electrophoresis
biopsies
PCR
density

Software Mentioned

Prism
DeltaVision
GraphPad
Improvision
OpenLab
Cell Quest

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