p150^glued deficiency impairs effective fusion between autophagosomes and lysosomes due to their redistribution to the cell periphery.

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.

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