The Pharmacological Chaperone 1-Deoxynojirimycin Increases the Activity and Lysosomal Trafficking of Multiple Mutant Forms of Acid Alpha-Glucosidase

被引:72
作者
Flanagan, John J. [2 ]
Rossi, Barbara [3 ]
Tang, Katherine [2 ]
Wu, Xiaoyang [2 ]
Mascioli, Kirsten [2 ]
Donaudy, Francesca [3 ]
Tuzzi, Maria Rosaria [1 ]
Fontana, Federica [1 ]
Cubellis, Maria Vittoria [4 ]
Porto, Caterina [1 ,3 ]
Benjamin, Elfrida [2 ]
Lockhart, David J. [2 ]
Valenzano, Kenneth J. [2 ]
Andria, Generoso [1 ]
Parenti, Giancarlo [1 ,3 ]
Do, Hung V. [2 ]
机构
[1] Univ Naples Federico II, Dept Pediat, I-80131 Naples, Italy
[2] Amicus Therapeut Inc, Cranbury, NJ 08512 USA
[3] Telethon Inst Genet & Med, Naples, Italy
[4] Univ Naples Federico II, Dept Struct & Funct Biol, I-80131 Naples, Italy
关键词
pharmacological chaperone; Pompe disease; acid alpha-glucosidase; GAA; deoxynojirimycin; DISEASE TYPE-II; ENZYME REPLACEMENT THERAPY; ONSET POMPE-DISEASE; INTRACELLULAR ENHANCEMENT; ISOFAGOMINE INCREASES; FABRY LYMPHOBLASTS; PROTEIN STRUCTURES; SKELETAL-MUSCLE; SWISS-MODEL; FIBROBLASTS;
D O I
10.1002/humu.21121
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA). Recently, small molecule pharmacological chaperones have been shown to increase protein stability and cellular levels for mutant lysosomal enzymes and have emerged as a new therapeutic strategy for the treatment of LSDs. In this study, we characterized the pharmacological chaperone 1-deoxynojirimycin (DNJ) on 76 different mutant forms of GAA identified in Pompe disease. DNJ significantly increased enzyme activity and protein levels for 16 different GAA mutants in patient-derived fibroblasts and in transiently transfected COS-7 cells. Additionally, DNJ increased the processing of these GAA mutants to their mature lysosomal forms, suggesting facilitated trafficking through the secretory pathway. Immunofluorescence microscopy studies showed increased colocalization of GAA with the lysosomal marker LAMP2 after incubation with DNJ, confirming increased lysosomal trafficking. Lastly, a GAA structural model was constructed based on the related eukaryotic glucosidase maltase-glucoamylase. The mutated residues identified in responsive forms of GAA are located throughout most of the structural domains, with half of these residues located in two short regions within the catalytic domain. Taken together, these data support further evaluation of DNJ as a potential treatment for Pompe disease in patients that express responsive forms of GAA. Hum Mutat 30:1683-1692, 2009. (C) 2009 Wiley-Liss, Inc.
引用
收藏
页码:1683 / 1692
页数:10
相关论文
共 57 条
[1]   In vitro inhibition and intracellular enhancement of lysosomal α-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives [J].
Asano, N ;
Ishii, S ;
Kizu, H ;
Ikeda, K ;
Yasuda, K ;
Kato, A ;
Martin, OR ;
Fan, JQ .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 2000, 267 (13) :4179-4186
[2]   The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines [J].
Benjamin, E. R. ;
Flanagan, J. J. ;
Schilling, A. ;
Chang, H. H. ;
Agarwal, L. ;
Katz, E. ;
Wu, X. ;
Pine, C. ;
Wustman, B. ;
Desnick, R. J. ;
Lockhart, D. J. ;
Valenzano, K. J. .
JOURNAL OF INHERITED METABOLIC DISEASE, 2009, 32 (03) :424-440
[3]   Recombinant human acid α-glucosidase:: high level production in mouse milk, biochemical characteristics, correction of enzyme deficiency in GSDII KO mice [J].
Bijvoet, AGA ;
Kroos, MA ;
Pieper, FR ;
Van der Vliet, M ;
De Boer, HA ;
Van der Ploeg, AT ;
Verbeet, MP ;
Reuser, AJJ .
HUMAN MOLECULAR GENETICS, 1998, 7 (11) :1815-1824
[4]  
Cardone Monica, 2008, Pathogenetics, V1, P6, DOI 10.1186/1755-8417-1-6
[5]   Distinguishing structural and functional restraints in evolution in order to identify interaction sites [J].
Chelliah, V ;
Chen, L ;
Blundell, TL ;
Lovell, SC .
JOURNAL OF MOLECULAR BIOLOGY, 2004, 342 (05) :1487-1504
[6]   Prediction of protein stability changes for single-site mutations using support vector machines [J].
Cheng, JL ;
Randall, A ;
Baldi, P .
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2006, 62 (04) :1125-1132
[7]  
CHENG Y, 1973, BIOCHEM PHARMACOL, V22, P3099
[8]   Secondary structure assignment that accurately reflects physical and evolutionary characteristics [J].
Cubellis, MV ;
Cailliez, F ;
Lovell, SC .
BMC BIOINFORMATICS, 2005, 6 (Suppl 4)
[9]   Neural deficits contribute to respiratory insufficiency in Pompe disease [J].
DeRuisseau, Lara R. ;
Fuller, David D. ;
Qiu, Kai ;
DeRuisseau, Keith C. ;
Donnelly, William H., Jr. ;
Mah, Cathryn ;
Reier, Paul J. ;
Byrne, Barry J. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (23) :9419-9424
[10]   Effects of non-contractile inclusions on mechanical performance of skeletal muscle [J].
Drost, MR ;
Hesselink, RP ;
Oomens, CW ;
van der Vusse, GJ .
JOURNAL OF BIOMECHANICS, 2005, 38 (05) :1035-1043