Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder
Inadequate glycogen branching enzyme 1 (GBE1) activity results in different forms of glycogen storage disease type IV, including adult polyglucosan body disorder (APBD). APBD is clinically characterized by adult-onset development of progressive spasticity, neuropathy, and neurogenic bladder and is h...
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| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2023.1261125/full |
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| author | Joseph R. Abraham Frederick M. Allen John Barnard Daniela Schlatzer Marvin R. Natowicz Marvin R. Natowicz |
| author_facet | Joseph R. Abraham Frederick M. Allen John Barnard Daniela Schlatzer Marvin R. Natowicz Marvin R. Natowicz |
| author_sort | Joseph R. Abraham |
| collection | DOAJ |
| description | Inadequate glycogen branching enzyme 1 (GBE1) activity results in different forms of glycogen storage disease type IV, including adult polyglucosan body disorder (APBD). APBD is clinically characterized by adult-onset development of progressive spasticity, neuropathy, and neurogenic bladder and is histologically characterized by the accumulation of structurally abnormal glycogen (polyglucosan bodies) in multiple cell types. How insufficient GBE1 activity causes the disease phenotype of APBD is poorly understood. We hypothesized that proteomic analysis of tissue from GBE1-deficient individuals would provide insights into GBE1-mediated pathobiology. In this discovery study, we utilized label-free LC–MS/MS to quantify the proteomes of lymphoblasts from 3 persons with APBD and 15 age- and gender-matched controls, with validation of the findings by targeted MS. There were 531 differentially expressed proteins out of 3,427 detected between APBD subjects vs. controls, including pronounced deficiency of GBE1. Bioinformatic analyses indicated multiple canonical pathways and protein–protein interaction networks to be statistically markedly enriched in APBD subjects, including: RNA processing/transport/translation, cell cycle control/replication, mTOR signaling, protein ubiquitination, unfolded protein and endoplasmic reticulum stress responses, glycolysis and cell death/apoptosis. Dysregulation of these processes, therefore, are primary or secondary factors in APBD pathobiology in this model system. Our findings further suggest that proteomic analysis of GBE1 mutant lymphoblasts can be leveraged as part of the screening for pharmaceutical agents for the treatment of APBD. |
| first_indexed | 2024-03-11T10:29:04Z |
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| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-03-11T10:29:04Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neurology |
| spelling | doaj.art-cecd2a120ed340e4a1be24e0cf1640a62023-11-15T05:13:42ZengFrontiers Media S.A.Frontiers in Neurology1664-22952023-11-011410.3389/fneur.2023.12611251261125Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorderJoseph R. Abraham0Frederick M. Allen1John Barnard2Daniela Schlatzer3Marvin R. Natowicz4Marvin R. Natowicz5Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United StatesCleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United StatesDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United StatesCenter for Proteomics, Case Western Reserve University School of Medicine, Cleveland, OH, United StatesCleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United StatesPathology and Laboratory Medicine, Genomic Medicine, Neurological and Pediatrics Institutes, Cleveland Clinic, Cleveland, OH, United StatesInadequate glycogen branching enzyme 1 (GBE1) activity results in different forms of glycogen storage disease type IV, including adult polyglucosan body disorder (APBD). APBD is clinically characterized by adult-onset development of progressive spasticity, neuropathy, and neurogenic bladder and is histologically characterized by the accumulation of structurally abnormal glycogen (polyglucosan bodies) in multiple cell types. How insufficient GBE1 activity causes the disease phenotype of APBD is poorly understood. We hypothesized that proteomic analysis of tissue from GBE1-deficient individuals would provide insights into GBE1-mediated pathobiology. In this discovery study, we utilized label-free LC–MS/MS to quantify the proteomes of lymphoblasts from 3 persons with APBD and 15 age- and gender-matched controls, with validation of the findings by targeted MS. There were 531 differentially expressed proteins out of 3,427 detected between APBD subjects vs. controls, including pronounced deficiency of GBE1. Bioinformatic analyses indicated multiple canonical pathways and protein–protein interaction networks to be statistically markedly enriched in APBD subjects, including: RNA processing/transport/translation, cell cycle control/replication, mTOR signaling, protein ubiquitination, unfolded protein and endoplasmic reticulum stress responses, glycolysis and cell death/apoptosis. Dysregulation of these processes, therefore, are primary or secondary factors in APBD pathobiology in this model system. Our findings further suggest that proteomic analysis of GBE1 mutant lymphoblasts can be leveraged as part of the screening for pharmaceutical agents for the treatment of APBD.https://www.frontiersin.org/articles/10.3389/fneur.2023.1261125/fulladult polyglucosan body diseaseGBE1glycogen branching enzymeglycogen storage diseaseneurodegenerationpathogenesis |
| spellingShingle | Joseph R. Abraham Frederick M. Allen John Barnard Daniela Schlatzer Marvin R. Natowicz Marvin R. Natowicz Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder Frontiers in Neurology adult polyglucosan body disease GBE1 glycogen branching enzyme glycogen storage disease neurodegeneration pathogenesis |
| title | Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder |
| title_full | Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder |
| title_fullStr | Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder |
| title_full_unstemmed | Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder |
| title_short | Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder |
| title_sort | proteomic investigations of adult polyglucosan body disease insights into the pathobiology of a neurodegenerative disorder |
| topic | adult polyglucosan body disease GBE1 glycogen branching enzyme glycogen storage disease neurodegeneration pathogenesis |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2023.1261125/full |
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