Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression

Walid Khrouf; Dario Saracino; Benoit Rucheton; Marion Houot; Fabienne Clot; Daisy Rinaldi; Joana Vitor; Marie Huynh; Evelyne Heng; Dimitri Schlemmer; Florence Pasquier; Vincent Deramecourt; Sophie Auriacombe; Carole Azuar; Richard Levy; Stéphanie Bombois; Claire Boutoleau-Brétonnière; Jérémie Pariente; Mira Didic; David Wallon; Frédérique Fluchère; Stéphane Auvin; Imen Ben Younes; Yann Nadjar; Alexis Brice; Bruno Dubois; Dominique Bonnefont-Rousselot; Isabelle Le Ber; Foudil Lamari

Neurobiology of Disease (Jun 2023)

Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression

Walid Khrouf,
Dario Saracino,
Benoit Rucheton,
Marion Houot,
Fabienne Clot,
Daisy Rinaldi,
Joana Vitor,
Marie Huynh,
Evelyne Heng,
Dimitri Schlemmer,
Florence Pasquier,
Vincent Deramecourt,
Sophie Auriacombe,
Carole Azuar,
Richard Levy,
Stéphanie Bombois,
Claire Boutoleau-Brétonnière,
Jérémie Pariente,
Mira Didic,
David Wallon,
Frédérique Fluchère,
Stéphane Auvin,
Imen Ben Younes,
Yann Nadjar,
Alexis Brice,
Bruno Dubois,
Dominique Bonnefont-Rousselot,
Isabelle Le Ber,
Foudil Lamari

Affiliations

Walid Khrouf: AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France
Dario Saracino: 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
Benoit Rucheton: AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France
Marion Houot: 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
Fabienne Clot: AP-HP.Sorbonne Université, Department of Genetics, UF of Molecular and Cellular Neurogenetics, - Hôpital Pitié-Salpêtrière, 75013 Paris, France
Daisy Rinaldi: 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
Joana Vitor: Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France
Marie Huynh: AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France
Evelyne Heng: AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France
Dimitri Schlemmer: AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France
Florence Pasquier: Univ Lille, Inserm 1172 LilNCOG, CHU Lille, CNR-MAJ, DistAlz, LiCEND 59000 Lille, France
Vincent Deramecourt: Univ Lille, Inserm 1172 LilNCOG, CHU Lille, CNR-MAJ, DistAlz, LiCEND 59000 Lille, France
Sophie Auriacombe: CMRR Nouvelle Aquitaine / Institut des Maladies Neurodégénératives clinique (IMNc), CHU de Bordeaux Hôpital Pellegrin, Bordeaux, France
Carole Azuar: AP-HP - Reference Centre for Rare or Early onset Dementias, IM2A, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France
Richard Levy: 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
Stéphanie Bombois: Univ Lille, Inserm 1172 LilNCOG, CHU Lille, CNR-MAJ, DistAlz, LiCEND 59000 Lille, France
Claire Boutoleau-Brétonnière: Centre Mémoire Ressource et Recherche (CMRR), Département de Neurologie, CHU Nantes, 44093 Nantes, France
Jérémie Pariente: Department of Neurology, Toulouse University Hospital, Toulouse, France; ToNIC, Toulouse NeuroImaging Centre, Inserm, UPS, University of Toulouse, Toulouse, France
Mira Didic: Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Marseille, France; APHM, Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France
David Wallon: Univ Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Neurology, CNR-MAJ, F 76000 Rouen, France
Frédérique Fluchère: APHM, Department of Neurology and Movement Disorders. La Timone, Clinical Neuroscience Unit, Aix-Marseille University, France
Stéphane Auvin: AP-HP, Robert-Debré University Hospital, Department of Pediatric Neurology, Paris, France
Imen Ben Younes: AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit - Hôpital Pitié-Salpêtrière, 75013 Paris, France
Yann Nadjar: AP-HP.Sorbonne Université, Neurology Department, Reference Center for Lysosomal Diseases, Hôpital Pitié-Salpêtrière, Paris, France
Alexis Brice: Sorbonne Université, Paris Brain Institute – Institut du Cerveau – ICM, Inserm U1127, CNRS UMR 7225, APHP - Hôpital Pitié-Salpêtrière, Paris, France
Bruno Dubois: 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
Dominique Bonnefont-Rousselot: 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
Isabelle Le Ber: 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; Correspondence to: I L Ber, Institut du Cerveau Paris (ICM), AP-HP - Hôpital Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital, 75013 Paris, France.
Foudil Lamari: 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; Correspondence to: F Lamari, AP-HP.Sorbonne Université, DMU Biogem-Metabolic Biochemistry department, Neurometabolic and Neurodegenerative Unit- Hôpital Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital, 75013 Paris, France.

Journal volume & issue: Vol. 181
p. 106108

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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