The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidaseResearch in context
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 cytoprotectiv...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-12-01
|
| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418305401 |
| _version_ | 1811193824156844032 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Cathrine K. Fog |
| collection | DOAJ |
| description | 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. Keywords: Gaucher disease, GBA, Heat shock response, Arimoclomol, Heat shock proteins, HSP, HSP70, Proteostasis, GCase, Lysosomes, Lysosomal storage diseases, Sphingolipidoses |
| first_indexed | 2024-04-12T00:15:54Z |
| format | Article |
| id | doaj.art-73a0c1f67b9c4c39af175f9198dbb0e8 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-12T00:15:54Z |
| publishDate | 2018-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-73a0c1f67b9c4c39af175f9198dbb0e82022-12-22T03:55:50ZengElsevierEBioMedicine2352-39642018-12-0138142153The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidaseResearch in contextCathrine K. Fog0Paola Zago1Erika Malini2Lukasz M. Solanko3Paolo Peruzzo4Claus Bornaes5Raffaella Magnoni6Arnela Mehmedbasic7Nikolaj H.T. Petersen8Bruno Bembi9Johannes F.M.G. Aerts10Andrea Dardis11Thomas Kirkegaard12Orphazyme A/S, Ole Maaloes vej 3, DK-2200 Copenhagen, DenmarkRegional Coordinator Centre for Rare Diseases, Academic Hospital “Santa Maria della Misericordia”, Udine, ItalyRegional Coordinator Centre for Rare Diseases, Academic Hospital “Santa Maria della Misericordia”, Udine, ItalyOrphazyme A/S, Ole Maaloes vej 3, DK-2200 Copenhagen, DenmarkRegional Coordinator Centre for Rare Diseases, Academic Hospital “Santa Maria della Misericordia”, Udine, ItalyOrphazyme A/S, Ole Maaloes vej 3, DK-2200 Copenhagen, DenmarkOrphazyme A/S, Ole Maaloes vej 3, DK-2200 Copenhagen, DenmarkOrphazyme A/S, Ole Maaloes vej 3, DK-2200 Copenhagen, DenmarkOrphazyme A/S, Ole Maaloes vej 3, DK-2200 Copenhagen, DenmarkRegional Coordinator Centre for Rare Diseases, Academic Hospital “Santa Maria della Misericordia”, Udine, ItalyLeiden Institute of Chemistry, Leiden University, Leiden, the NetherlandsRegional Coordinator Centre for Rare Diseases, Academic Hospital “Santa Maria della Misericordia”, Udine, ItalyOrphazyme A/S, Ole Maaloes vej 3, DK-2200 Copenhagen, Denmark; Corresponding author.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. Keywords: Gaucher disease, GBA, Heat shock response, Arimoclomol, Heat shock proteins, HSP, HSP70, Proteostasis, GCase, Lysosomes, Lysosomal storage diseases, Sphingolipidoseshttp://www.sciencedirect.com/science/article/pii/S2352396418305401 |
| spellingShingle | 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 The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidaseResearch in context EBioMedicine |
| title | The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidaseResearch in context |
| title_full | The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidaseResearch in context |
| title_fullStr | The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidaseResearch in context |
| title_full_unstemmed | The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidaseResearch in context |
| title_short | The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidaseResearch in context |
| title_sort | heat shock protein amplifier arimoclomol improves refolding maturation and lysosomal activity of glucocerebrosidaseresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396418305401 |
| work_keys_str_mv | AT cathrinekfog theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT paolazago theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT erikamalini theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT lukaszmsolanko theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT paoloperuzzo theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT clausbornaes theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT raffaellamagnoni theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT arnelamehmedbasic theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT nikolajhtpetersen theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT brunobembi theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT johannesfmgaerts theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT andreadardis theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT thomaskirkegaard theheatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT cathrinekfog heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT paolazago heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT erikamalini heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT lukaszmsolanko heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT paoloperuzzo heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT clausbornaes heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT raffaellamagnoni heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT arnelamehmedbasic heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT nikolajhtpetersen heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT brunobembi heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT johannesfmgaerts heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT andreadardis heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext AT thomaskirkegaard heatshockproteinamplifierarimoclomolimprovesrefoldingmaturationandlysosomalactivityofglucocerebrosidaseresearchincontext |