학술논문
Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression.
Document Type
Academic Journal
Author
Khrouf W; AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France.; Saracino D; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France; Aramis Project Team, Inria Research Center of Paris, Paris, France; AP-HP - Reference Centre for Rare or Early onset Dementias, IM2A, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.; Rucheton B; AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France.; Houot M; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France; AP-HP - Reference Centre for Rare or Early onset Dementias, IM2A, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France; Centre of Excellence of Neurodegenerative Disease (CoEN), Hôpital Pitié-Salpêtrière, Paris, France.; Clot F; AP-HP.Sorbonne Université, Department of Genetics, UF of Molecular and Cellular Neurogenetics, - Hôpital Pitié-Salpêtrière, 75013 Paris, France.; Rinaldi D; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France; AP-HP - Reference Centre for Rare or Early onset Dementias, IM2A, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.; Vitor J; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.; Huynh M; AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France.; Heng E; AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France.; Schlemmer D; AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France.; Pasquier F; Univ Lille, Inserm 1172 LilNCOG, CHU Lille, CNR-MAJ, DistAlz, LiCEND 59000 Lille, France.; Deramecourt V; Univ Lille, Inserm 1172 LilNCOG, CHU Lille, CNR-MAJ, DistAlz, LiCEND 59000 Lille, France.; Auriacombe S; CMRR Nouvelle Aquitaine / Institut des Maladies Neurodégénératives clinique (IMNc), CHU de Bordeaux Hôpital Pellegrin, Bordeaux, France.; Azuar C; AP-HP - Reference Centre for Rare or Early onset Dementias, IM2A, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.; Levy R; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France; AP-HP - Reference Centre for Rare or Early onset Dementias, IM2A, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.; Bombois S; Univ Lille, Inserm 1172 LilNCOG, CHU Lille, CNR-MAJ, DistAlz, LiCEND 59000 Lille, France.; Boutoleau-Brétonnière C; Centre Mémoire Ressource et Recherche (CMRR), Département de Neurologie, CHU Nantes, 44093 Nantes, France.; Pariente J; Department of Neurology, Toulouse University Hospital, Toulouse, France; ToNIC, Toulouse NeuroImaging Centre, Inserm, UPS, University of Toulouse, Toulouse, France.; Didic M; Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Marseille, France; APHM, Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France.; Wallon D; Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Neurology, CNR-MAJ, F 76000 Rouen, France.; Fluchère F; APHM, Department of Neurology and Movement Disorders. La Timone, Clinical Neuroscience Unit, Aix-Marseille University, France.; Auvin S; AP-HP, Robert-Debré University Hospital, Department of Pediatric Neurology, Paris, France.; Younes IB; AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France.; Nadjar Y; AP-HP.Sorbonne Université, Neurology Department, Reference Center for Lysosomal Diseases, Hôpital Pitié-Salpêtrière, Paris, France.; Brice A; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.; Dubois B; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France; AP-HP - Reference Centre for Rare or Early onset Dementias, IM2A, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.; Bonnefont-Rousselot D; AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France; Université Paris Cité, UTCBS, U 1022 Inserm, UMR 8258 CNRS, Paris University, Paris, France.; Le Ber I; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France; AP-HP - Reference Centre for Rare or Early onset Dementias, IM2A, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France. Electronic address: isabelle.leber@upmc.fr.; Lamari F; AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France; Sorbonne Université, Paris Brain Institute - Institut du Cerveau - ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France.
Source
Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE
Subject
Language
English
Abstract
GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases. We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography. Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers. This study evidences an age-dependent increase of β-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)