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P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway.

ABSTRACT: Mutations in p150glued cause hereditary motor neuropathy with vocal cord paralysis (HMN7B) and Perry syndrome (PS). Here we show that both overexpression of p150glued mutants and knockdown of endogenous p150glued induce apoptosis. Overexpression of a p150glued plasmid containing either a HMN7B or PS mutation resulted in cytoplasmic p150glued-positive aggregates and was associated with cell death. Cells containing mutant p150glued aggregates underwent apoptosis that was characterized by an increase in cleaved caspase-3- or Annexin V-positive cells and was attenuated by both zVAD-fmk (a pan-caspase inhibitor) application and caspase-3 siRNA knockdown. In addition, overexpression of mutant p150glued decreased mitochondrial membrane potentials and increased levels of translocase of the mitochondrial outer membrane (Tom20) protein, indicating accumulation of damaged mitochondria. Importantly, siRNA knockdown of endogenous p150glued independently induced apoptosis via caspase-8 activation and was not associated with mitochondrial morphological changes. Simultaneous knockdown of endogenous p150glued and overexpression of mutant p150glued had additive apoptosis induction effects. These findings suggest that both p150glued gain-of-toxic-function and loss-of-physiological-function can cause apoptosis and may underlie the pathogenesis of p150glued-associated disorders.

SUBMITTER: Ishikawa K

PROVIDER: S-EPMC3983229 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway.

Ishikawa Kei-Ichi K Saiki Shinji S Furuya Norihiko N Yamada Daisuke D Imamichi Yoko Y Li Yuanzhe Y Kawajiri Sumihiro S Sasaki Hironori H Koike Masato M Tsuboi Yoshio Y Hattori Nobutaka N

PloS one 20140410 4

Mutations in p150glued cause hereditary motor neuropathy with vocal cord paralysis (HMN7B) and Perry syndrome (PS). Here we show that both overexpression of p150glued mutants and knockdown of endogenous p150glued induce apoptosis. Overexpression of a p150glued plasmid containing either a HMN7B or PS mutation resulted in cytoplasmic p150glued-positive aggregates and was associated with cell death. Cells containing mutant p150glued aggregates underwent apoptosis that was characterized by an increa ...[more]

PMID: 24722468

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P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway.

Publications

P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway.

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