Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis
Abstract Bi-allelic pathogenic GBA1 variants cause Gaucher disease (GD), whereas certain heterozygous missense variants increase the risk of Parkinson’s disease (PD), although the underlying mechanisms are unclear. Here, we classified GBA1 missense variants using predictive and structural scores, an...
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Nature Portfolio
2025-08-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-01060-6 |
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| author | Aymeric Lanore Christelle Tesson Aymeric Basset François-Xavier Lejeune Guillaume Cogan Graziella Mangone Sara Sambin Nathalie Bertille Mathieu Anheim Isabelle Arnulf Solène Ansquer Jean-Philippe Brandel Christine Brefel-Courbon Luc Defebvre Sophie Drapier Alexandre Eusebsio Margherita Fabbri Caroline Giordana Elodie Hainque Stephane Lehericy Ana Marques Caroline Moreau Elena Moro Fabienne Ory Anne-Sophie Rolland Stéphane Thobois Marie Vidailhet David Devos Louise-Laure Mariani Suzanne Lesage Alexis Brice Jean-Christophe Corvol for the Predistim study group the Iceberg study group the NSPark study group |
| author_facet | Aymeric Lanore Christelle Tesson Aymeric Basset François-Xavier Lejeune Guillaume Cogan Graziella Mangone Sara Sambin Nathalie Bertille Mathieu Anheim Isabelle Arnulf Solène Ansquer Jean-Philippe Brandel Christine Brefel-Courbon Luc Defebvre Sophie Drapier Alexandre Eusebsio Margherita Fabbri Caroline Giordana Elodie Hainque Stephane Lehericy Ana Marques Caroline Moreau Elena Moro Fabienne Ory Anne-Sophie Rolland Stéphane Thobois Marie Vidailhet David Devos Louise-Laure Mariani Suzanne Lesage Alexis Brice Jean-Christophe Corvol for the Predistim study group the Iceberg study group the NSPark study group |
| author_sort | Aymeric Lanore |
| collection | DOAJ |
| description | Abstract Bi-allelic pathogenic GBA1 variants cause Gaucher disease (GD), whereas certain heterozygous missense variants increase the risk of Parkinson’s disease (PD), although the underlying mechanisms are unclear. Here, we classified GBA1 missense variants using predictive and structural scores, and analysed their associations with enzyme activity, Saposin C (SapC) interaction and PD progression in 639 patients with heterozygous GBA1 variants from five cohorts. Principal component analysis (PCA) identified two components: PC1, associated with reduced β-glucocerebosidase activity, the GD clinical severity classification, younger age at PD diagnosis, and faster cognitive and motor decline; and PC2, associated with surface-exposed, flexible regions involved in SapC interactions, younger age at PD diagnosis, and slightly with motor decline. These findings highlight that impaired SapC interactions, in addition to reduced activity, may contribute to PD severity in GBA1 variant carriers. This is relevant for therapeutic approaches aimed at stabilizing β-glucocerebosidase or enhancing its enzymatic activity in PD. |
| format | Article |
| id | doaj-art-3053b5253a2c43a08d2ff646cfbb962a |
| institution | Kabale University |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-3053b5253a2c43a08d2ff646cfbb962a2025-08-20T03:46:03ZengNature Portfolionpj Parkinson's Disease2373-80572025-08-0111111410.1038/s41531-025-01060-6Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysisAymeric Lanore0Christelle Tesson1Aymeric Basset2François-Xavier Lejeune3Guillaume Cogan4Graziella Mangone5Sara Sambin6Nathalie Bertille7Mathieu Anheim8Isabelle Arnulf9Solène Ansquer10Jean-Philippe Brandel11Christine Brefel-Courbon12Luc Defebvre13Sophie Drapier14Alexandre Eusebsio15Margherita Fabbri16Caroline Giordana17Elodie Hainque18Stephane Lehericy19Ana Marques20Caroline Moreau21Elena Moro22Fabienne Ory23Anne-Sophie Rolland24Stéphane Thobois25Marie Vidailhet26David Devos27Louise-Laure Mariani28Suzanne Lesage29Alexis Brice30Jean-Christophe Corvol31for the Predistim study groupthe Iceberg study groupthe NSPark study groupSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreAP-HP, Hôpital Pitié Salpêtrière, Centre de Pharmacoépidémiologie (Cephepi), CIC-1901Department of Neurology, Neurogenetic Reference Centre, Parkinson’s Expert Centre, University Hospitals of StrasbourgSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreNeurology Department, Centre Expert Parkinson, CIC-INSERM 1402, CHU PoitiersHôpital Fondation Ophtalmologique A de Rothschild, Unité James Parkisnon, NS-PARK/FCRIN NetworkClinical Investigation Center CIC1436, Parkinson Expert Center, Department of Clinical, Pharmacology and Neuroscience, NS-Park/FCRIN network, NeuroToul COEN Center; Toulouse, University Hospital, INSERM and University of Toulouse 3Parkinson’s Disease Center of Excellence, Department of Neurology, University of Lille, CHU Lille, INSERM U1172- Degenerative & Vascular Cognitive DisordersPontchaillou University Hospital, Department of Neurology, CIC INSERM 1414Aix Marseille Université, AP-HM, Hôpital de La Timone, Service de Neurologie et Pathologie du MouvementClinical Investigation Center CIC1436, Parkinson Expert Center, Department of Clinical, Pharmacology and Neuroscience, NS-Park/FCRIN network, NeuroToul COEN Center; Toulouse, University Hospital, INSERM and University of Toulouse 3Neurology Department, NS-Park/FCRIN network, Centre Hospitalier Universitaire de Nice, Université Côte d’AzurSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreAssistance Publique Hôpitaux de Paris, Department of Neuroradiology, Hôpital Pitié-SalpêtrièreUniversité Clermont Auvergne, IGCNC, Department of Neurology, Parkinson expert center, CHU Clermont-FerrandParkinson’s Disease Center of Excellence, Department of Neurology, University of Lille, CHU Lille, INSERM U1172- Degenerative & Vascular Cognitive DisordersGrenoble Alpes University, Movement Disorders Unit, Division of Neurology, CHU de Grenoble, Grenoble Institute of NeurosciencesClinical Investigation Center CIC1436, Parkinson Expert Center, Department of Clinical, Pharmacology and Neuroscience, NS-Park/FCRIN network, NeuroToul COEN Center; Toulouse, University Hospital, INSERM and University of Toulouse 3Department of Medical Pharmacology, CHU Lille, University of Lille, Lille Neuroscience & Cognition, INSERM, UMR-S1172, LICEND, NS-Park/F-CRIN networkHospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Department of Neurology C, NS-Park/FCRIN network, Univ Lyon, Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Sud Charles Mérieux, Lyon, France; INSERM, Centre de Recherche en Neurosciences de Lyon, PATH-PARKSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreDepartment of Medical Pharmacology, CHU Lille, University of Lille, Lille Neuroscience & Cognition, INSERM, UMR-S1172, LICEND, NS-Park/F-CRIN networkSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreSorbonne Université, Institut du Cerveau – Paris Brain Institute – ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, NS-Park/FCRIN network, Department of Neurology, CIC Neurosciences, Hôpital Pitié-SalpêtrièreAbstract Bi-allelic pathogenic GBA1 variants cause Gaucher disease (GD), whereas certain heterozygous missense variants increase the risk of Parkinson’s disease (PD), although the underlying mechanisms are unclear. Here, we classified GBA1 missense variants using predictive and structural scores, and analysed their associations with enzyme activity, Saposin C (SapC) interaction and PD progression in 639 patients with heterozygous GBA1 variants from five cohorts. Principal component analysis (PCA) identified two components: PC1, associated with reduced β-glucocerebosidase activity, the GD clinical severity classification, younger age at PD diagnosis, and faster cognitive and motor decline; and PC2, associated with surface-exposed, flexible regions involved in SapC interactions, younger age at PD diagnosis, and slightly with motor decline. These findings highlight that impaired SapC interactions, in addition to reduced activity, may contribute to PD severity in GBA1 variant carriers. This is relevant for therapeutic approaches aimed at stabilizing β-glucocerebosidase or enhancing its enzymatic activity in PD.https://doi.org/10.1038/s41531-025-01060-6 |
| spellingShingle | Aymeric Lanore Christelle Tesson Aymeric Basset François-Xavier Lejeune Guillaume Cogan Graziella Mangone Sara Sambin Nathalie Bertille Mathieu Anheim Isabelle Arnulf Solène Ansquer Jean-Philippe Brandel Christine Brefel-Courbon Luc Defebvre Sophie Drapier Alexandre Eusebsio Margherita Fabbri Caroline Giordana Elodie Hainque Stephane Lehericy Ana Marques Caroline Moreau Elena Moro Fabienne Ory Anne-Sophie Rolland Stéphane Thobois Marie Vidailhet David Devos Louise-Laure Mariani Suzanne Lesage Alexis Brice Jean-Christophe Corvol for the Predistim study group the Iceberg study group the NSPark study group Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis npj Parkinson's Disease |
| title | Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis |
| title_full | Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis |
| title_fullStr | Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis |
| title_full_unstemmed | Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis |
| title_short | Classification of GBA1 variants and their impact on Parkinson’s disease: an in silico score analysis |
| title_sort | classification of gba1 variants and their impact on parkinson s disease an in silico score analysis |
| url | https://doi.org/10.1038/s41531-025-01060-6 |
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