The Heat Shock Protein Amplifier Arimoclomol Improves Refolding, Maturation and Lysosomal Activity of Glucocerebrosidase

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2018 Dec 1

PMID 30497978

Citations 24

Authors

Cathrine K Fog

Paola Zago

Erika Malini

Lukasz M Solanko

Paolo Peruzzo

Claus Bornaes

Raffaella Magnoni

Arnela Mehmedbasic

Nikolaj H T Petersen

Bruno Bembi

Johannes F M G Aerts

Andrea Dardis

Thomas Kirkegaard

Affiliations

Soon will be listed here.

Abstract

Background: Gaucher Disease is caused by mutations of the GBA gene which encodes the lysosomal enzyme acid beta-glucosidase (GCase). GBA mutations commonly affect GCase function by perturbing its protein homeostasis rather than its catalytic activity. Heat shock proteins are well known cytoprotective molecules with functions in protein homeostasis and lysosomal function and their manipulation has been suggested as a potential therapeutic strategy for GD. The investigational drug arimoclomol, which is in phase II/III clinical trials, is a well-characterized HSP amplifier and has been extensively clinically tested. Importantly, arimoclomol efficiently crosses the blood-brain-barrier presenting an opportunity to target the neurological manifestations of GD, which remains without a disease-modifying therapy.

Methods: We used a range of biological and biochemical in vitro assays to assess the effect of arimoclomol on GCase activity in ex vivo systems of primary fibroblasts and neuronal-like cells from GD patients.

Findings: We found that arimoclomol induced relevant HSPs such as ER-resident HSP70 (BiP) and enhanced the folding, maturation, activity, and correct cellular localization of mutated GCase across several genotypes including the common L444P and N370S mutations in primary cells from GD patients. These effects where recapitulated in a human neuronal model of GD obtained by differentiation of multipotent adult stem cells.

Interpretation: These data demonstrate the potential of HSP-targeting therapies in GCase-deficiencies and strongly support the clinical development of arimoclomol as a potential therapeutic option for the neuronopathic forms of GD.

Funding: The research was funded by Orphazyme A/S, Copenhagen, Denmark.

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References

Beutler E, Gelbart T, KUHL W, Sorge J, West C . Identification of the second common Jewish Gaucher disease mutation makes possible population-based screening for the heterozygous state. Proc Natl Acad Sci U S A. 1991; 88(23):10544-7. PMC: 52965. DOI: 10.1073/pnas.88.23.10544. View

Cherin P, Rose C, de Roux-Serratrice C, Tardy D, Dobbelaere D, Grosbois B . The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG). J Inherit Metab Dis. 2010; 33(4):331-8. DOI: 10.1007/s10545-010-9095-5. View

Mahat D, Salamanca H, Duarte F, Danko C, Lis J . Mammalian Heat Shock Response and Mechanisms Underlying Its Genome-wide Transcriptional Regulation. Mol Cell. 2016; 62(1):63-78. PMC: 4826300. DOI: 10.1016/j.molcel.2016.02.025. View

Maegawa G, Tropak M, Buttner J, Rigat B, Fuller M, Pandit D . Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem. 2009; 284(35):23502-16. PMC: 2749124. DOI: 10.1074/jbc.M109.012393. View

Wang F, Segatori L . Remodeling the proteostasis network to rescue glucocerebrosidase variants by inhibiting ER-associated degradation and enhancing ER folding. PLoS One. 2013; 8(4):e61418. PMC: 3631227. DOI: 10.1371/journal.pone.0061418. View

Weiss K, Gonzalez A, Lopez G, Pedoeim L, Groden C, Sidransky E . The clinical management of Type 2 Gaucher disease. Mol Genet Metab. 2014; 114(2):110-122. PMC: 4312716. DOI: 10.1016/j.ymgme.2014.11.008. View

Rosenbloom B, Balwani M, Bronstein J, Kolodny E, Sathe S, Gwosdow A . The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry. Blood Cells Mol Dis. 2010; 46(1):95-102. PMC: 4662380. DOI: 10.1016/j.bcmd.2010.10.006. View

Cudkowicz M, Shefner J, Simpson E, Grasso D, Yu H, Zhang H . Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. Muscle Nerve. 2008; 38(1):837-44. DOI: 10.1002/mus.21059. View

Jian J, Tian Q, Hettinghouse A, Zhao S, Liu H, Wei J . Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease. EBioMedicine. 2016; 13:212-224. PMC: 5264254. DOI: 10.1016/j.ebiom.2016.10.010. View

10.

Kalmar B, Edet-Amana E, Greensmith L . Treatment with a coinducer of the heat shock response delays muscle denervation in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012; 13(4):378-92. DOI: 10.3109/17482968.2012.660953. View

11.

Yang C, Swallows C, Zhang C, Lu J, Xiao H, Brady R . Celastrol increases glucocerebrosidase activity in Gaucher disease by modulating molecular chaperones. Proc Natl Acad Sci U S A. 2013; 111(1):249-54. PMC: 3890874. DOI: 10.1073/pnas.1321341111. View

12.

Maor G, Rencus-Lazar S, Filocamo M, Steller H, Segal D, Horowitz M . Unfolded protein response in Gaucher disease: from human to Drosophila. Orphanet J Rare Dis. 2013; 8:140. PMC: 3819655. DOI: 10.1186/1750-1172-8-140. View

13.

Gyrd-Hansen M, Farkas T, Fehrenbacher N, Bastholm L, Hoyer-Hansen M, Elling F . Apoptosome-independent activation of the lysosomal cell death pathway by caspase-9. Mol Cell Biol. 2006; 26(21):7880-91. PMC: 1636747. DOI: 10.1128/MCB.00716-06. View

14.

Alcalay R, Levy O, Waters C, Fahn S, Ford B, Kuo S . Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. Brain. 2015; 138(Pt 9):2648-58. PMC: 4564023. DOI: 10.1093/brain/awv179. View

15.

Patten S, Hughes H, Huff M, Piepenhagen P, Waire J, Qiu H . Effect of mannose chain length on targeting of glucocerebrosidase for enzyme replacement therapy of Gaucher disease. Glycobiology. 2007; 17(5):467-78. DOI: 10.1093/glycob/cwm008. View

16.

Bendikov-Bar I, Ron I, Filocamo M, Horowitz M . Characterization of the ERAD process of the L444P mutant glucocerebrosidase variant. Blood Cells Mol Dis. 2010; 46(1):4-10. DOI: 10.1016/j.bcmd.2010.10.012. View

17.

Kirkegaard T, Gray J, Priestman D, Wallom K, Atkins J, Olsen O . Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci Transl Med. 2016; 8(355):355ra118. PMC: 6821533. DOI: 10.1126/scitranslmed.aad9823. View

18.

Reczek D, Schwake M, Schroder J, Hughes H, Blanz J, Jin X . LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell. 2007; 131(4):770-83. DOI: 10.1016/j.cell.2007.10.018. View

19.

Tylki-Szymanska A, Vellodi A, El-Beshlawy A, Cole J, Kolodny E . Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry. J Inherit Metab Dis. 2010; 33(4):339-46. DOI: 10.1007/s10545-009-9009-6. View

20.

Whitfield P, Nelson P, Sharp P, Bindloss C, Dean C, Ravenscroft E . Correlation among genotype, phenotype, and biochemical markers in Gaucher disease: implications for the prediction of disease severity. Mol Genet Metab. 2002; 75(1):46-55. DOI: 10.1006/mgme.2001.3269. View