title: A motor neuron disease-associated mutation in p150Glued perturbs dynactin function and induces protein aggregation.
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.
authors.affiliation: Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Levy
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Sumner
authors.forename: Juliane P
authors.initials: JP
authors.lastname: Caviston
authors.forename: Mariko K
authors.initials: MK
authors.lastname: Tokito
authors.forename: Srikanth
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Lee A
authors.initials: LA
authors.lastname: Ligon
authors.forename: Karen E
authors.initials: KE
authors.lastname: Wallace
authors.forename: Bernadette H
authors.initials: BH
authors.lastname: LaMonte
authors.forename: George G
authors.initials: GG
authors.lastname: Harmison
authors.forename: Imke
authors.initials: I
authors.lastname: Puls
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D008870:Microtubules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism*; D017354:Point Mutation
chemical_list: D000072159:Dynactin Complex; D018840:HSP70 Heat-Shock Proteins; C500985:MAPRE1 protein, human; D008869:Microtubule-Associated Proteins; D004398:Dyneins