title: Proteasome Inhibitor Bortezomib Enhances the Activity of Multiple Mutant Forms of Lysosomal α-Glucosidase in Pompe Disease.
abstract: Pompe disease is an autosomal recessive myopathic disorder caused by the deficiency of lysosomal acid α-glucosidase (GAA). Recently, we showed that function of mutant GAA in fibroblasts derived from Pompe disease patient carrying c.546G>T mutation is improved by treatment with proteasome inhibitor bortezomib as well as pharmacological chaperone (PC). However, bortezomib-responsive GAA mutations are not fully characterized. In this study, we showed the effect of bortezomib on different mutants of GAA in patient fibroblasts and transiently expressed HEK293T cells. Bortezomib increased the maturation and residual activity of GAA in patient fibroblasts carrying PC-responsive M519V and PC-unresponsive C647W mutations. Enhanced colocalization of GAA with lysosomal marker LAMP2 was also observed in patient fibroblasts after treatment with bortezomib. When four distinct mutant GAAs, which show different response to PC, were overexpressed in HEK293T cells, bortezomib improved the activity of M519V, S529V, and C647W in them (1.3-5.9-fold). These results indicate that bortezomib enhances the activity of some PC-unresponsive GAA mutants as well as PC-responsive mutants.
authors.affiliation: Division of Gene Therapy, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, 105-8461, Japan, shimada_y@jikei.ac.jp.
authors.forename: Yohta
authors.initials: Y
authors.lastname: Shimada
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura
authors.forename: Hiroo
authors.initials: H
authors.lastname: Hoshina
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Higuchi
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Eto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ida
authors.forename: Toya
authors.initials: T
authors.lastname: Ohashi