P150glued deficiency impairs effective fusion between autophagosomes and lysosomes due to their redistribution to the cell periphery. (18th January 2019)

• Record Type: Journal Article
• Authors: Ishikawa, Kei-ichi; Saiki, Shinji; Furuya, Norihiko; Imamichi, Yoko; Tsuboi, Yoshio; Hattori, Nobutaka
• Is Part Of: Neuroscience letters. Volume 690(2019)
• Page Start: 181
• Page End: 187
• Publication Date: 2019-01-18
• Subjects: HMN7B hereditary motor neuronopathy with vocal paresis -- PS Perry syndrome -- iPSCs induced pluripotent stem cells -- ALS amyotrophic lateral sclerosis -- KD knockdown -- mTORC1 mammalian target of rapamycin complex 1 -- PI3K phosphoinositide 3-kinase; Dynactin -- P150glued -- Autophagy -- Perry syndrome -- Lysosome -- Autophagosome; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2018.10.036
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Lysosomes and autophagosomes redistribute to periphery of p150 glued mutant cells. Lysosomes and autophagosomes redistribute to cell periphery in p150 glued -KD cells. Autolysosome formation occurs in p150 glued -KD cells despite organelle redistribution. Decreased autophagosome-lysosome fusion in starved p150 glued -KD cells. Abstract: Dynein-dynactin has an indispensable role in autophagy and p150 glued is the largest component of the dynactin complex. Here, we characterized the effects of knockdown (KD) of endogenous p150 glued and of the pathogenic mutation of p150 glued found in autosomal dominant p150 glued -associated disorders [hereditary motor neuronopathy with vocal paresis (HMN7B) and Perry syndrome] on autophagy. Overexpression of the p150 glued pathogenic mutant or siRNA KD of p150 glued promoted the localization of lysosomes at the cell periphery and increased the number of autophagosomes, suggesting partial blockage of autophagic flux. Surprisingly, although autophagosomes and lysosomes were redistributed predominantly to the cell periphery in p150 glued -KD cells, the autolysosome formation ratio was preserved. However, under autophagy activation conditions induced by starvation, the ratio of autophagosome-lysosome fusion in p150 glued -KD cells was decreased in the early phase. Our data demonstrate that functional loss of p150 glued may cause autophagic insufficiency, which may be associated with the pathogenesis of p150 glued -associated disorders.