Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder

Joseph R Abraham; Frederick M Allen; John Barnard; Daniela Schlatzer; Marvin R Natowicz

doi:10.3389/fneur.2023.1261125

Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder

Front Neurol. 2023 Nov 14:14:1261125. doi: 10.3389/fneur.2023.1261125. eCollection 2023.

Authors

Joseph R Abraham¹, Frederick M Allen¹, John Barnard², Daniela Schlatzer³, Marvin R Natowicz^{1

4}

Affiliations

¹ Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States.
² Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.
³ Center for Proteomics, Case Western Reserve University School of Medicine, Cleveland, OH, United States.
⁴ Pathology and Laboratory Medicine, Genomic Medicine, Neurological and Pediatrics Institutes, Cleveland Clinic, Cleveland, OH, United States.

Abstract

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.

Keywords: GBE1; adult polyglucosan body disease; glycogen branching enzyme; glycogen storage disease; lymphoblast; neurodegeneration; pathogenesis; proteomic.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by funding from the Coddon Family Foundation and the Pathology & Laboratory Medicine Institute of the Cleveland Clinic.