title: Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics.
abstract: Axonal damage is a prominent cause of disability and yet its pathogenesis is incompletely understood. Using a xenogeneic system, here we define the bioenergetic changes induced in rat neurons by exposure to cerebrospinal fluid samples from patients with multiple sclerosis compared to control subjects. A first discovery cohort of cerebrospinal fluid from 13 patients with multiple sclerosis and 10 control subjects showed that acute exposure to cerebrospinal fluid from patients with multiple sclerosis induced oxidative stress and decreased expression of neuroprotective genes, while increasing expression of genes involved in lipid signalling and in the response to oxidative stress. Protracted exposure of neurons to stress led to neurotoxicity and bioenergetics failure after cerebrospinal fluid exposure and positively correlated with the levels of neurofilament light chain. These findings were validated using a second independent cohort of cerebrospinal fluid samples (eight patients with multiple sclerosis and eight control subjects), collected at a different centre. The toxic effect of cerebrospinal fluid on neurons was not attributable to differences in IgG content, glucose, lactate or glutamate levels or differences in cytokine levels. A lipidomic profiling approach led to the identification of increased levels of ceramide C16:0 and C24:0 in the cerebrospinal fluid from patients with multiple sclerosis. Exposure of cultured neurons to micelles composed of these ceramide species was sufficient to recapitulate the bioenergetic dysfunction and oxidative damage induced by exposure to cerebrospinal fluid from patients with multiple sclerosis. Therefore, our data suggest that C16:0 and C24:0 ceramides are enriched in the cerebrospinal fluid of patients with multiple sclerosis and are sufficient to induce neuronal mitochondrial dysfunction and axonal damage.
authors.affiliation: 1 Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Oscar G
authors.initials: OG
authors.lastname: Vidaurre
authors.affiliation: 1 Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Haines
authors.affiliation: 2 Corinne Goldsmith Dickinson Centre for MS, Mount Sinai Medical Centre, New York, NY 10029, USA.
authors.forename: Ilana
authors.initials: I
authors.lastname: Katz Sand
authors.affiliation: 1 Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Kadidia P
authors.initials: KP
authors.lastname: Adula
authors.affiliation: 1 Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jimmy L
authors.initials: JL
authors.lastname: Huynh
authors.affiliation: 3 Department of Neurology, Albert Einstein College of Medicine, Montefiore Medical Centre, Bronx, NY, USA.
authors.forename: Corey A
authors.initials: CA
authors.lastname: McGraw
authors.affiliation: 4 Bioinformatics Department, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 5 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Merina
authors.initials: M
authors.lastname: Varghese
authors.affiliation: 6 Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Sotirchos
authors.affiliation: 6 Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Bhargava
authors.affiliation: 6 Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Veera Venkata Ratnam
authors.initials: VV
authors.lastname: Bandaru
authors.affiliation: 5 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Pasinetti
authors.affiliation: 4 Bioinformatics Department, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 7 Department of Neurology, Radiology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Matilde
authors.initials: M
authors.lastname: Inglese
authors.affiliation: 6 Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.affiliation: 8 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: 2 Corinne Goldsmith Dickinson Centre for MS, Mount Sinai Medical Centre, New York, NY 10029, USA.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Miller
authors.affiliation: 6 Department of Neurology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Haughey
authors.affiliation: 2 Corinne Goldsmith Dickinson Centre for MS, Mount Sinai Medical Centre, New York, NY 10029, USA.
authors.forename: Fred D
authors.initials: FD
authors.lastname: Lublin
authors.affiliation: 1 Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA patrizia.casaccia@mssm.edu.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000134:cerebrospinal fluid* / Q000633:toxicity*; D015331:Cohort Studies; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D002518:Ceramides
keywords: axonal degeneration; demyelinating disease; lipid metabolism; mitochondria; neurodegenerative mechanism