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

dc.rights.licenseopenen_US
dc.contributor.authorKHROUF, Walid
dc.contributor.authorSARACINO, Dario
dc.contributor.authorRUCHETON, Benoit
dc.contributor.authorHOUOT, Marion
dc.contributor.authorCLOT, Fabienne
dc.contributor.authorRINALDI, Daisy
dc.contributor.authorVITOR, Joana
dc.contributor.authorHUYNH, Marie
dc.contributor.authorHENG, Evelyne
dc.contributor.authorSCHLEMMER, Dimitri
dc.contributor.authorPASQUIER, Florence
dc.contributor.authorDERAMECOURT, Vincent
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorAURIACOMBE, Sophie
dc.contributor.authorAZUAR, Carole
dc.contributor.authorLEVY, Richard
dc.contributor.authorBOMBOIS, Stephanie
dc.contributor.authorBOUTOLEAU-BRETONNIERE, Claire
dc.contributor.authorPARIENTE, Jeremie
dc.contributor.authorDIDIC, Mira
dc.contributor.authorWALLON, David
dc.contributor.authorFLUCHERE, Frederique
dc.contributor.authorAUVIN, Stephane
dc.contributor.authorBEN YOUNES, Imen
dc.contributor.authorNADJAR, Yann
dc.contributor.authorBRICE, Alexis
dc.contributor.authorDUBOIS, Bruno
dc.contributor.authorBONNEFONT-ROUSSELOT, Dominique
dc.contributor.authorLE BER, Isabelle
dc.contributor.authorLAMARI, Foudil
dc.contributor.authorBELLIARD, Serge
dc.contributor.authorBLANC, Frederic
dc.contributor.authorCECCALDI, Mathieu
dc.contributor.authorCOURATIER, Philippe
dc.contributor.authorETCHARRY-BOUYX, Frederique
dc.contributor.authorFORMAGLIO, Maite
dc.contributor.authorGOLFIER, Veronique
dc.contributor.authorHANNEQUIN, Didier
dc.contributor.authorLACOMBLEZ, Lucette
dc.contributor.authorLAGARDE, Julien
dc.contributor.authorMICHEL, Bernard-Francois
dc.contributor.authorROUE-JAGOT, Carole
dc.contributor.authorSELLAL, Francois
dc.contributor.authorTHAUVIN-ROBINET, Christel
dc.contributor.authorTHOMAS-ANTERION, Catherine
dc.contributor.authorVERCELLETTO, Martine
dc.contributor.authorGIRARD, Nadine
dc.contributor.authorGUEDJ, Eric
dc.contributor.authorPUEL, Michele
dc.contributor.authorBERRY, Isabelle
dc.contributor.authorPAYOUX, Pierre
dc.contributor.authorAUFFRAY-CALVIER, Elisabeth
dc.contributor.authorPALLARDY, Amandine
dc.contributor.authorLEBOUVIER, Thibaud
dc.contributor.authorROLLIN, Adeline
dc.contributor.authorKUCHINSKI, Gregory
dc.contributor.authorMARTINAUD, Olivier
dc.contributor.authorGERARDIN, Emmanuel
dc.contributor.authorVERA, Pierre
dc.contributor.authorCAMUZAT, Agnes
dc.contributor.authorCHUPIN, Marie
dc.contributor.authorBARDINET, Eric
dc.contributor.authorKAS, Aurelie
dc.contributor.authorLEMERCIER, Valerie-Causse
dc.contributor.authorMASMANIAN, Merry
dc.contributor.authorOYA, Herve
dc.date.accessioned2023-04-18T08:42:07Z
dc.date.available2023-04-18T08:42:07Z
dc.date.issued2023-06-01
dc.identifier.issn1095-953X (Electronic) 0969-9961 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/173046
dc.description.abstractEnGRN 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.
dc.description.sponsorshipInfrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciencesen_US
dc.language.isoENen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subject.enrontotemporal dementia (FTD)
dc.subject.enNeuronal ceroid lipofuscinosis-11 (CLN-11)
dc.subject.enProgranulin
dc.subject.enLysosphingolipids
dc.subject.enLysosome
dc.subject.enLysosomal storage disease (LSD)
dc.title.enPlasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression
dc.title.alternativeNeurobiol Disen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1016/j.nbd.2023.106108en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed37003407en_US
bordeaux.journalNeurobiology of Diseaseen_US
bordeaux.volume181en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamACTIVE_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-04072526
hal.version1
hal.date.transferred2023-04-18T08:42:41Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&amp;rft_val_fmt=info:ofi/fmt:kev:mtx:journal&amp;rft.jtitle=Neurobiology%20of%20Disease&amp;rft.date=2023-06-01&amp;rft.volume=181&amp;rft.eissn=1095-953X%20(Electronic)%200969-9961%20(Linking)&amp;rft.issn=1095-953X%20(Electronic)%200969-9961%20(Linking)&amp;rft.au=KHROUF,%20Walid&amp;SARACINO,%20Dario&amp;RUCHETON,%20Benoit&amp;HOUOT,%20Marion&amp;CLOT,%20Fabienne&amp;rft.genre=article


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