Wild-Type DCTN1 Suppresses the Aggregation of DCTN1 Mutants Associated with Perry Disease.

Abstract

Perry disease, a rare autosomal dominant neurodegenerative disorder, is characterized by parkinsonism, depression or apathy, unexpected weight loss, and central hypoventilation. Genetic analyses have revealed a strong association between point mutations in the dynactin I gene (DCTN1) coding p150^glued and Perry disease. Although previous reports have suggested a critical role of p150^glued aggregation in Perry disease pathology, whether and how p150^glued mutations affect protein aggregation is not fully understood. In this study, we comprehensively investigated the intracellular distribution of the p150^glued mutants in HEK293T cells. We further assessed the effect of co-overexpression of the wild-type p150^glued protein with mutants on the formation of mutant aggregates. Notably, overexpression of p150^glued mutants identified in healthy controls, which is also associated with amyotrophic lateral sclerosis, showed a thread-like cytoplasmic distribution, similar to the wild-type p150^glued. In contrast, p150^glued mutants in Perry disease and motor neuron disease caused aggregation. In addition, the co-overexpression of the wild-type protein with p150^glued mutants in Perry disease suppressed aggregate formation. In contrast, the p150^glued aggregation of motor neuron disease mutants was less affected by the wild-type p150^glued. Further investigation of the mechanism of aggregate formation, contents of the aggregates, and biological mechanisms of Perry disease could help develop novel therapeutics.