{"doi":"10.1073/pnas.192582899","title":"Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease","abstract":"<jats:p>\n                    Gaucher disease is a lysosomal storage disorder caused by deficient lysosomal β-glucosidase (β-Glu) activity. A marked decrease in enzyme activity results in progressive accumulation of the substrate (glucosylceramide) in macrophages, leading to hepatosplenomegaly, anemia, skeletal lesions, and sometimes CNS involvement. Enzyme replacement therapy for Gaucher disease is costly and relatively ineffective for CNS involvement. Chemical chaperones have been shown to stabilize various proteins against misfolding, increasing proper trafficking from the endoplasmic reticulum. We report herein that the addition of subinhibitory concentrations (10 μM) of\n                    <jats:italic>N</jats:italic>\n                    -(\n                    <jats:italic>n</jats:italic>\n                    -nonyl)deoxynojirimycin (NN-DNJ) to a fibroblast culture medium for 9 days leads to a 2-fold increase in the activity of N370S β-Glu, the most common mutation causing Gaucher disease. Moreover, the increased activity persists for at least 6 days after the withdrawal of the putative chaperone. The NN-DNJ chaperone also increases WT β-Glu activity, but not that of L444P, a less prevalent Gaucher disease variant. Incubation of isolated soluble WT enzyme with NN-DNJ reveals that β-Glu is stabilized against heat denaturation in a dose-dependent fashion. We propose that NN-DNJ chaperones β-Glu folding at neutral pH, thus allowing the stabilized enzyme to transit from the endoplasmic reticulum to the Golgi, enabling proper trafficking to the lysosome. Clinical data suggest that a modest increase in β-Glu activity may be sufficient to achieve a therapeutic effect.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2002,"id":42912,"datarank":13.294273998897841,"base_score":6.222576268071369,"endowment":6.222576268071369,"self_citation_contribution":0.9333864402107055,"citation_network_contribution":12.360887558687136,"self_endowment_contribution":0.9333864402107055,"citer_contribution":12.360887558687136,"corpus_percentile":null,"corpus_rank":null,"citation_count":503,"citer_count":200,"citers_with_citation_signal":200,"citers_with_endowment":200,"datacite_reuse_total":6,"is_dataset":false,"is_dataset_confidence":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":67.5,"fair_percentile":95.13259483048003,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":204661,"name":"Wei-Chieh Cheng","orcid":null,"position":1,"is_corresponding":false},{"id":204430,"name":"Ernest Beutler","orcid":null,"position":2,"is_corresponding":false},{"id":133196,"name":"Chi-Huey Wong","orcid":null,"position":3,"is_corresponding":false},{"id":122146,"name":"William E. Balch","orcid":null,"position":4,"is_corresponding":false},{"id":145286,"name":"Jeffery W. Kelly","orcid":null,"position":5,"is_corresponding":false},{"id":204660,"name":"Anu R. Sawkar","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":6.222576268071369,"endowment":6.222576268071369,"datacite_reuse_total":6,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"12434014","pmcid":"PMC137733","openalex_id":"https://openalex.org/W1758125525","authors":[],"funders":[],"total_grants":0,"fwci":10.5295,"citation_percentile":0.98956712,"influential_citations":20,"citation_trend":[{"year":2012,"count":26},{"year":2013,"count":26},{"year":2014,"count":29},{"year":2015,"count":13},{"year":2016,"count":25},{"year":2017,"count":13},{"year":2018,"count":19},{"year":2019,"count":12},{"year":2020,"count":11},{"year":2021,"count":14},{"year":2022,"count":14},{"year":2023,"count":10},{"year":2024,"count":11},{"year":2025,"count":10},{"year":2026,"count":3}],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/137733","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc137733?pdf=render","host_type":"GREEN"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/137733","host_type":"repository"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.192582899","host_type":"publisher"},{"url":"https://doi.org/10.1073/pnas.192582899","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/12434014","host_type":"repository"}],"fields_of_study":["Lysosomal Storage Disorders Research","Carbohydrate Chemistry and Synthesis","Cellular transport and secretion","Medicine","Biology","Chemistry","1-Deoxynojirimycin","Alkylation","Amino Acid Substitution","Cells, Cultured","Dose-Response Relationship, Drug","Endoplasmic Reticulum","Fibroblasts","Gaucher Disease","Golgi Apparatus","Heterocyclic Compounds","Humans","Hydrogen-Ion Concentration","Lysosomes","Molecular Structure","Morpholines","Protein Denaturation","Protein Folding","Protein Transport","Structure-Activity Relationship","beta-Glucosidase"],"mesh_terms":["Alkylation","beta-Glucosidase","Cells, Cultured","Dose-Response Relationship, Drug","Endoplasmic Reticulum","Fibroblasts","Gaucher Disease","Golgi Apparatus","Heterocyclic Compounds","Humans","Hydrogen-Ion Concentration","Lysosomes","Morpholines","Protein Denaturation","Structure-Activity Relationship","Molecular Structure","1-Deoxynojirimycin","Protein Folding","Amino Acid Substitution","Protein Transport"],"keywords":["Chemical chaperone","Endoplasmic reticulum","Glucocerebrosidase","Enzyme","Lysosomal storage disease","Chaperone (clinical)","Substrate reduction therapy","Glucocerebroside","Enzyme replacement therapy","Biochemistry","Hepatosplenomegaly","Lysosome","Golgi apparatus","ER retention","Enzyme assay","Biology","Chemistry","Unfolded protein response","Disease","Medicine","Internal medicine","Mutant","Pathology"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[{"doi":"10.6084/m9.figshare.26574724.v1","title":"Additional file 2 of SMPD1 expression profile and mutation landscape help decipher genotype–phenotype association and precision diagnosis for acid sphingomyelinase deficiency","publisher":"figshare","resource_type":"Dataset"},{"doi":"10.6084/m9.figshare.26574721","title":"Additional file 1 of SMPD1 expression profile and mutation landscape help decipher genotype–phenotype association and precision diagnosis for acid sphingomyelinase 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