Title :

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

Author(s) :

Khrouf, Walid [Auteur]
Saracino, Dario [Auteur]
Rucheton, Benoit [Auteur]
Houot, Marion [Auteur]
Clot, Fabienne [Auteur]
Rinaldi, Daisy [Auteur]
Vitor, Joana [Auteur]
Huynh, Marie [Auteur]
Heng, Evelyne [Auteur]
Schlemmer, Dimitri [Auteur]
Pasquier, Florence [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Deramecourt, Vincent [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Auriacombe, Sophie [Auteur]
Azuar, Carole [Auteur]
Levy, Richard [Auteur]
Bombois, Stephanie [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Boutoleau-Brétonnière, Claire [Auteur]
Pariente, Jérémie [Auteur]
Didic, Mira [Auteur]
Wallon, David [Auteur]
Fluchère, Frédérique [Auteur]
Auvin, Stéphane [Auteur]
Ben Younes, Imen [Auteur]
Nadjar, Yann [Auteur]
Brice, Alexis [Auteur]
Dubois, Bruno [Auteur]
Bonnefont-Rousselot, Dominique [Auteur]
Le Ber, Isabelle [Auteur]
Lamari, Foudil [Auteur]
Belliard, Serge [Auteur]
Blanc, Frédéric [Auteur]
Ceccaldi, Mathieu [Auteur]
Couratier, Philippe [Auteur]
Etcharry-Bouyx, Frédérique [Auteur]
Formaglio, Maïté [Auteur]
Golfier, Véronique [Auteur]
Lacomblez, Lucette [Auteur]
Lagarde, Julien [Auteur]
Michel, Bernard-François [Auteur]
Roué-Jagot, Carole [Auteur]
Sellal, François [Auteur]
Thauvin-Robinet, Christel [Auteur]
Thomas-Antérion, Catherine [Auteur]
Vercelletto, Martine [Auteur]
Girard, Nadine [Auteur]
Guedj, Eric [Auteur]
Puel, Michèle [Auteur]
Berry, Isabelle [Auteur]
Payoux, Pierre [Auteur]
Boutoleau-Brétonnière, C. [Auteur]
Auffray-Calvier, Elisabeth [Auteur]
Pallardy, Amandine [Auteur]
Lebouvier, Thibaud [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Martinaud, Olivier [Auteur]
Gerardin, Emmanuel [Auteur]
Camuzat, Agnes [Auteur]
Chupin, Marie [Auteur]
Kas, Aurélie [Auteur]
Lemercier, Valérie-Causse [Auteur]
Masmanian, Merry [Auteur]
Oya, Hervé [Auteur]

Journal title :

Neurobiology of Disease

Abbreviated title :

Neurobiol Dis

Volume number :

181

Pages :

106108

Publisher :

Elsevier

Publication date :

2023-06-01

ISSN :

1095-953X

English keyword(s) :

Frontotemporal dementia (FTD)
Neuronal ceroid lipofuscinosis-11 (CLN-11)
Progranulin
Lysosphingolipids
Lysosome
Lysosomal storage disease (LSD)

HAL domain(s) :

Sciences du Vivant [q-bio]
Sciences du Vivant [q-bio]/Santé publique et épidémiologie

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

ANR Project :

Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Lille Neurosciences & Cognition (LilNCog) - U 1172

Research team(s) :

Troubles cognitifs dégénératifs et vasculaires

Submission date :

2024-01-15T23:13:49Z
2024-12-02T14:10:28Z