High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson's disease.

Glucosylceramidase / metabolism Humans Gaucher Disease / drug therapy Parkinson Disease / drug therapy High-Throughput Screening Assays / methods Protein Folding / drug effects Small Molecule Libraries / pharmacology Cell Line, Tumor
Gaucher disease Parkinson’s disease glucocerebrosidase high-throughput screening pharmacological chaperone

Journal

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876

Informations de publication

Date de publication:
15 Oct 2024
Historique:
medline: 10 10 2024
pubmed: 10 10 2024
entrez: 10 10 2024
Statut: ppublish

Résumé

Glucocerebrosidase (GCase) is implicated in both a rare, monogenic disorder (Gaucher disease, GD) and a common, multifactorial condition (Parkinson's disease, PD); hence, it is an urgent therapeutic target. To identify correctors of severe protein misfolding and trafficking obstruction manifested by the pathogenic L444P-variant of GCase, we developed a suite of quantitative, high-throughput, cell-based assays. First, we labeled GCase with a small proluminescent HiBiT peptide reporter tag, enabling quantitation of protein stabilization in cells while faithfully maintaining target biology. TALEN-based gene editing allowed for stable integration of a single HiBiT-

Identifiants

DOI: 10.1073/pnas.2406009121 PMID: 39388267
pubmed: 39388267
doi: 10.1073/pnas.2406009121
doi:

Substances chimiques

Glucosylceramidase EC 3.2.1.45
Small Molecule Libraries 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2406009121

Subventions

Organisme : Michael J. Fox Foundation for Parkinson's Research (MJFF)
ID : MJFF-021673

Déclaration de conflit d'intérêts

Competing interests statement:A.G. and R.J. are employees of F. Hoffmann-La Roche AG.

Auteurs

Darian Williams (D)

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.

Logan M Glasstetter (LM)

Molecular Neurogenetics Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892.

Tiffany T Jong (TT)

Molecular Neurogenetics Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892.

Tiffany Chen (T)

Molecular Neurogenetics Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892.
ORCID: 0009-0007-9297-1988

Abhijeet Kapoor (A)

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.

Sha Zhu (S)

Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
ORCID: 0000-0003-3352-1040

Yanping Zhu (Y)

Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.

Raul Calvo (R)

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.
ORCID: 0000-0001-5967-1296

Alexandra Gehrlein (A)

Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland.
ORCID: 0000-0003-4901-7316

Kimberly Wong (K)

Molecular Neurogenetics Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892.
ORCID: 0009-0006-8865-9660

Andrew N Hogan (AN)

Molecular Neurogenetics Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892.

David J Vocadlo (DJ)

Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
ORCID: 0000-0001-6897-5558

Ravi Jagasia (R)

Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, 4070 Basel, Switzerland.

Juan J Marugan (JJ)

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.
ORCID: 0000-0002-3951-7061

Ellen Sidransky (E)

Molecular Neurogenetics Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892.
ORCID: 0000-0002-3019-8500

Mark J Henderson (MJ)

Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.
ORCID: 0000-0001-8590-7338

Yu Chen (Y)

Molecular Neurogenetics Section, Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892.
ORCID: 0000-0001-5438-7309

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Glycosidases › Glucosidases › Glucosylceramidase › High-throughput screening for small-molecule...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › High-throughput screening for small-molecule...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Erreurs innées du métabolisme › Maladies lysosomiales › Maladies neurologiques de surcharge lysosomiale › Sphingolipidoses › Maladie de Gaucher › High-throughput screening for small-molecule...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › High-throughput screening for small-molecule...
questionsmedicales.fr › Techniques d'investigation › Tests de criblage à haut débit › High-throughput screening for small-molecule...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Pliage des protéines › High-throughput screening for small-molecule...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Bibliothèques de petites molécules › High-throughput screening for small-molecule...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › High-throughput screening for small-molecule...