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.
Competing interests: None declared
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Acknowledgments
We are grateful to Genzyme Corporation for the supply of anti-GAA antibody and to our colleagues in the Division of Gene Therapy for their excellent technical assistance. This work was supported by Grant-in-Aid for Young Scientists (B) JSPS KAKENHI Grant Number 24791089 from the Ministry of Education, Science, Sports, and Culture of Japan (Y.S.).
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Communicated by: Gregory M. Pastores, MD
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Synopsis
Bortezomib improves the function of multiple GAA mutants in Pompe disease.
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Yoshikatsu Eto has received grant support from Genzyme Corporation.
Hiroyuki Ida has received grant support from Genzyme Corporation.
Toya Ohashi has received grant support from Genzyme Corporation.
Yohta Shimada, Erica Nishimura, Hiroo Hoshina, Hiroshi Kobayashi, and Takashi Higuchi declare that they have no conflict of interest.
These activities have been fully disclosed and are managed under a Memorandum of Understanding with the Conflict of Interest Resolution Board of the Jikei University School of Medicine.
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
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This article does not contain any studies with animal subjects performed by any of the authors.
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Y.S. and T.O. designed and conducted research; Y.S., E.N., and H.H. performed experiments and analyzed data; Y.S. wrote the paper; and H.K., T.H., Y.E., H.I., and T.O. discussed data and edited the paper.
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Shimada, Y. et al. (2014). Proteasome Inhibitor Bortezomib Enhances the Activity of Multiple Mutant Forms of Lysosomal α-Glucosidase in Pompe Disease. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 18. JIMD Reports, vol 18. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_345
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DOI: https://doi.org/10.1007/8904_2014_345
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