Lysosomal storage diseases are treated with human lysosomal enzymes produced in mammalian cells. Such enzyme therapeutics contain relatively low levels of mannose-6-phosphate, which is required to target them to the lysosomes of patient cells. Here we describe a method for increasing mannose-6-phosphate modification of lysosomal enzymes produced in yeast. We identified a glycosidase from C. cellulans that 'uncaps' N-glycans modified by yeast-type mannose-Pi-6-mannose to generate mammalian-type N-glycans with a mannose-6-phosphate substitution. Determination of the crystal structure of this glycosidase provided insight into its substrate specificity. We used this uncapping enzyme together with α-mannosidase to produce in yeast a form of the Pompe disease enzyme α-glucosidase rich in mannose-6-phosphate. Compared with the currently used therapeutic version, this form of α-glucosidase was more efficiently taken up by fibroblasts from Pompe disease patients, and it more effectively reduced cardiac muscular glycogen storage in a mouse model of the disease.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/nbt.2427 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Differences in Blood and Cerebrospinal Fluid Between Parkinson's Disease and Related Diseases.
Cell Mol Neurobiol
December 2024
Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
It is difficult to distinguish Parkinson's disease (PD) in the early stage from those of various disorders including atypical Parkinson's syndrome (APS), vascular parkinsonism (VP), and even essential tremor (ET), because of the overlap of symptoms. Other, more challenging problems will arise when Parkinson's disease develops into Parkinson's disease dementia (PDD) in the middle and late stages. At this time, the differential diagnosis of PDD and DLB becomes thorny.
View Article and Find Full Text PDFNewborn Screening for Acid Sphingomyelinase Deficiency: Prevalence and Genotypic Findings in Italy.
Int J Neonatal Screen
December 2024
Division of Inherited Metabolic Diseases, Department of Women's and Children's Health, University Hospital of Padua, 35128 Padua, Italy.
Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with a broad clinical spectrum. Early diagnosis and initiation of treatment are crucial for improving outcomes, yet the disease often goes undiagnosed due to its rarity and phenotypic heterogeneity. This study aims to evaluate the feasibility and disease incidence of newborn screening (NBS) for ASMD in Italy.
View Article and Find Full Text PDFPDGFR-α shRNA-polyplex for uveal melanoma treatment via EMT mediated vasculogenic mimicry interfering.
J Nanobiotechnology
December 2024
National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
Up to 50% of individuals with uveal melanoma (UM), a frequent cancer of the eye, pass away from metastases. One of the major challenges in treating UM is the role of receptor tyrosine kinases (RTKs), which mediate the epithelial-mesenchymal transition (EMT) of tumors. RTKs are involved in binding multiple growth factors, leading to angiogenesis and vasculogenic mimicry (VM) phenomena.
View Article and Find Full Text PDFHSP90 stabilizes visual cycle retinol dehydrogenase 5 in the endoplasmic reticulum by inhibiting its degradation during autophagy.
J Biol Chem
December 2024
The Laboratory of Ophthalmology and Vision Science, Department of Ophthalmology, The Joint National Laboratory of Antibody Drug Engineering, Henan Province Engineering Research Center of Fundus Disease and Ocular Trauma Prevention and Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China; Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, Zhengzhou, China; Kaifeng Key Lab for Cataracts and Myopia, Kaifeng Central Hospital, Kaifeng, China; Eye Institute, Henan Academy of Innovations in Medical Science, Zhengzhou, China. Electronic address:
Genetic mutations in retinol dehydrogenase 5 (RDH5), a rate-limiting enzyme of the visual cycle, is associated with nyctalopia, AMD and stationary congenital fundus albipunctatus (FA). A majority of these mutations impair RDH5 protein expression and intracellular localization. However, the regulatory mechanisms underlying RDH5 metabolism remain unclear.
View Article and Find Full Text PDFClinical, Pathological, and Molecular Findings in a Mexican Patient With Neuronal Ceroid Lipofuscinosis Type 2: Support for Pathogenicity of the c.1226 G>T Variant and for Presence of Cherry-Red Spot in This Disease.
Pediatr Dev Pathol
December 2024
Department of Human Genetics, National Institute of Pediatrics, Mexico City, Mexico.
Neuronal ceroid lipofuscinosis type 2 (CLN2) results from biallelic pathogenic variants in the gene, leading to deficient activity of the lysosomal enzyme tripeptidyl peptidase 1. We report an autopsy case of CLN2 characterized at molecular level. The patient exhibited a spectrum of neurologic symptoms including epilepsy, behavioral alterations, cognitive regression, motor impairment, and visual loss.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!