2024/02/09 by Na Zhang, Fuchen Liu, Yuying Zhao +6 · 6 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Biochemistry #Biology #Chemistry #Enzyme #Genetics and Neurodevelopmental Disorders #Glycogen #Glycogen Storage Diseases and Myoclonus #Glycogen branching enzyme #Glycogen debranching enzyme #Glycogen storage disease #Glycogen synthase #Glycogenolysis #Lysosomal Storage Disorders Research #Lysosome
paper · doi:10.1002/path.6255
published in The Journal of Pathology 263(1), 8-21
openalex publication_date 2024/02/09 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
Abstract Pompe disease is a lysosomal storage disorder that preferentially affects muscles, and it is caused by GAA mutation coding acid alpha‐glucosidase in lysosome and glycophagy deficiency. While the initial pathology of Pompe disease is glycogen accumulation in lysosomes, the special role of the lysosomal pathway in glycogen degradation is not fully understood. Hence, we investigated the characteristics of accumulated glycogen and the mechanism underlying glycophagy disturbance in Pompe disease. Skeletal muscle specimens were obtained from the affected sites of patients and mouse models with Pompe disease. Histological analysis, immunoblot analysis, immunofluorescence assay, and lysosome isolation were utilized to analyze the characteristics of accumulated glycogen. Cell culture, lentiviral infection, and the CRISPR/Cas9 approach were utilized to investigate the regulation of glycophagy accumulation. We demonstrated residual glycogen, which was distinguishable from mature glycogen by exposed glycogenin and more α‐amylase resistance, accumulated in the skeletal muscle of Pompe disease. Lysosome isolation revealed glycogen‐free glycogenin in wild type mouse lysosomes and variously sized glycogenin in Gaa −/− mouse lysosomes. Our study identified that a defect in the degradation of glycogenin‐exposed residual glycogen in lysosomes was the fundamental pathological mechanism of Pompe disease. Meanwhile, glycogenin‐exposed residual glycogen was absent in other glycogen storage diseases caused by cytoplasmic glycogenolysis deficiencies. In vitro , the generation of residual glycogen resulted from cytoplasmic glycogenolysis. Notably, the inhibition of glycogen phosphorylase led to a reduction in glycogenin‐exposed residual glycogen and glycophagy accumulations in cellular models of Pompe disease. Therefore, the lysosomal hydrolysis pathway played a crucial role in the degradation of residual glycogen into glycogenin, which took place in tandem with cytoplasmic glycogenolysis. These findings may offer a novel substrate reduction therapeutic strategy for Pompe disease. © 2024 The Pathological Society of Great Britain and Ireland.