title: Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis.
abstract: Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS). To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles) had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT), in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL) thickness and of the macular volume (MV) after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI) evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS.
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy ; Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bozzali
authors.affiliation: Dipartimento di Medicina Sperimentale e Chirurgia, Università Tor Vergata, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Bari
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy ; Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mori
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy ; Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy ; Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy ; Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Buttari
authors.affiliation: Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy ; Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex, United Kingdom.
authors.forename: Mara
authors.initials: M
authors.lastname: Cercignani
authors.affiliation: Dipartimento Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gravina
authors.affiliation: Dipartimento di Medicina Sperimentale e Chirurgia, Università Tor Vergata, Rome, Italy.
authors.forename: Nicolina
authors.initials: N
authors.lastname: Mastrangelo
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy ; Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Castelli
authors.affiliation: Clinica Oculistica, Dipartimento di Biopatologia, Università Tor Vergata, Rome, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Mancino
authors.affiliation: Clinica Oculistica, Dipartimento di Biopatologia, Università Tor Vergata, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Nucci
authors.affiliation: IRCCS Centro Neurolesi Bonino Pulejo, Messina, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Sottile
authors.affiliation: Dipartimento Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy ; Dipartimento di Medicina Interna, Università Tor Vergata, Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
authors.affiliation: Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy ; Center of Integrated Research, School of Medicine, Campus Bio-Medico University of Rome, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy ; Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000328:Adult; D001284:Atrophy; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D003071:Cognition; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009900:Optic Nerve / Q000473:pathology / Q000503:physiopathology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000502:physiology; D018911:Trinucleotide Repeats
chemical_list: C571130:CNR1 protein, human; D043884:Receptor, Cannabinoid, CB1