Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts
Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate...
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| Autor*in: |
Cardone, Monica [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2008 |
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| Anmerkung: |
© Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
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| Übergeordnetes Werk: |
Enthalten in: Pathogenetics - London : BioMed Central, 2008, 1(2008), 1 vom: 01. Dez. |
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| Übergeordnetes Werk: |
volume:1 ; year:2008 ; number:1 ; day:01 ; month:12 |
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| DOI / URN: |
10.1186/1755-8417-1-6 |
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| Katalog-ID: |
SPR030164478 |
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| 520 | |a Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. | ||
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10.1186/1755-8417-1-6 doi (DE-627)SPR030164478 (SPR)1755-8417-1-6-e DE-627 ger DE-627 rakwb eng Cardone, Monica verfasserin aut Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. Enzyme Replacement Therapy (dpeaa)DE-He213 Late Endosome (dpeaa)DE-He213 Pompe Disease (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Rabbit Polyclonal Antiserum (dpeaa)DE-He213 Porto, Caterina aut Tarallo, Antonietta aut Vicinanza, Mariella aut Rossi, Barbara aut Polishchuk, Elena aut Donaudy, Francesca aut Andria, Generoso aut De Matteis, Maria Antonietta aut Parenti, Giancarlo aut Enthalten in Pathogenetics London : BioMed Central, 2008 1(2008), 1 vom: 01. Dez. (DE-627)585798141 (DE-600)2467114-9 1755-8417 nnns volume:1 year:2008 number:1 day:01 month:12 https://dx.doi.org/10.1186/1755-8417-1-6 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 1 2008 1 01 12 |
| spelling |
10.1186/1755-8417-1-6 doi (DE-627)SPR030164478 (SPR)1755-8417-1-6-e DE-627 ger DE-627 rakwb eng Cardone, Monica verfasserin aut Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. Enzyme Replacement Therapy (dpeaa)DE-He213 Late Endosome (dpeaa)DE-He213 Pompe Disease (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Rabbit Polyclonal Antiserum (dpeaa)DE-He213 Porto, Caterina aut Tarallo, Antonietta aut Vicinanza, Mariella aut Rossi, Barbara aut Polishchuk, Elena aut Donaudy, Francesca aut Andria, Generoso aut De Matteis, Maria Antonietta aut Parenti, Giancarlo aut Enthalten in Pathogenetics London : BioMed Central, 2008 1(2008), 1 vom: 01. Dez. (DE-627)585798141 (DE-600)2467114-9 1755-8417 nnns volume:1 year:2008 number:1 day:01 month:12 https://dx.doi.org/10.1186/1755-8417-1-6 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 1 2008 1 01 12 |
| allfields_unstemmed |
10.1186/1755-8417-1-6 doi (DE-627)SPR030164478 (SPR)1755-8417-1-6-e DE-627 ger DE-627 rakwb eng Cardone, Monica verfasserin aut Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. Enzyme Replacement Therapy (dpeaa)DE-He213 Late Endosome (dpeaa)DE-He213 Pompe Disease (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Rabbit Polyclonal Antiserum (dpeaa)DE-He213 Porto, Caterina aut Tarallo, Antonietta aut Vicinanza, Mariella aut Rossi, Barbara aut Polishchuk, Elena aut Donaudy, Francesca aut Andria, Generoso aut De Matteis, Maria Antonietta aut Parenti, Giancarlo aut Enthalten in Pathogenetics London : BioMed Central, 2008 1(2008), 1 vom: 01. Dez. (DE-627)585798141 (DE-600)2467114-9 1755-8417 nnns volume:1 year:2008 number:1 day:01 month:12 https://dx.doi.org/10.1186/1755-8417-1-6 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 1 2008 1 01 12 |
| allfieldsGer |
10.1186/1755-8417-1-6 doi (DE-627)SPR030164478 (SPR)1755-8417-1-6-e DE-627 ger DE-627 rakwb eng Cardone, Monica verfasserin aut Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. Enzyme Replacement Therapy (dpeaa)DE-He213 Late Endosome (dpeaa)DE-He213 Pompe Disease (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Rabbit Polyclonal Antiserum (dpeaa)DE-He213 Porto, Caterina aut Tarallo, Antonietta aut Vicinanza, Mariella aut Rossi, Barbara aut Polishchuk, Elena aut Donaudy, Francesca aut Andria, Generoso aut De Matteis, Maria Antonietta aut Parenti, Giancarlo aut Enthalten in Pathogenetics London : BioMed Central, 2008 1(2008), 1 vom: 01. Dez. (DE-627)585798141 (DE-600)2467114-9 1755-8417 nnns volume:1 year:2008 number:1 day:01 month:12 https://dx.doi.org/10.1186/1755-8417-1-6 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 1 2008 1 01 12 |
| allfieldsSound |
10.1186/1755-8417-1-6 doi (DE-627)SPR030164478 (SPR)1755-8417-1-6-e DE-627 ger DE-627 rakwb eng Cardone, Monica verfasserin aut Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts 2008 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. Enzyme Replacement Therapy (dpeaa)DE-He213 Late Endosome (dpeaa)DE-He213 Pompe Disease (dpeaa)DE-He213 Control Fibroblast (dpeaa)DE-He213 Rabbit Polyclonal Antiserum (dpeaa)DE-He213 Porto, Caterina aut Tarallo, Antonietta aut Vicinanza, Mariella aut Rossi, Barbara aut Polishchuk, Elena aut Donaudy, Francesca aut Andria, Generoso aut De Matteis, Maria Antonietta aut Parenti, Giancarlo aut Enthalten in Pathogenetics London : BioMed Central, 2008 1(2008), 1 vom: 01. Dez. (DE-627)585798141 (DE-600)2467114-9 1755-8417 nnns volume:1 year:2008 number:1 day:01 month:12 https://dx.doi.org/10.1186/1755-8417-1-6 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 1 2008 1 01 12 |
| language |
English |
| source |
Enthalten in Pathogenetics 1(2008), 1 vom: 01. Dez. volume:1 year:2008 number:1 day:01 month:12 |
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abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in pompe disease fibroblasts |
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Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts |
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Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. © Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
| abstractGer |
Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. © Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
| abstract_unstemmed |
Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. Conclusion These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols. © Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR030164478</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519174829.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s2008 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/1755-8417-1-6</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR030164478</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)1755-8417-1-6-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Cardone, Monica</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2008</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© Cardone et al; licensee BioMed Central Ltd. 2008. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Background Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself. Results We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced. 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