title: Cerebellar compartmentation of prion pathogenesis.
abstract: In prion diseases, the brain lesion profile is influenced by the prion "strain" properties, the invasion route to the brain, and still unknown host cell-specific parameters. To gain insight into those endogenous factors, we analyzed the histopathological alterations induced by distinct prion strains in the mouse cerebellum. We show that 22L and ME7 scrapie prion proteins (PrP22L, PrPME7), but not bovine spongiform encephalopathy PrP6PB1, accumulate in a reproducible parasagittal banding pattern in the cerebellar cortex of infected mice. Such banding pattern of PrP22Laggregation did not depend on the neuroinvasion route, but coincided with the parasagittal compartmentation of the cerebellum mostly defined by the expression of zebrins, such as aldolase C and the excitatory amino acid transporter 4, in Purkinje cells. We provide evidence that Purkinje cells display a differential, subtype-specific vulnerability to 22L prions with zebrin-expressing Purkinje cells being more resistant to prion toxicity, while in stripes where PrP22Laccumulated most zebrin-deficient Purkinje cells are lost and spongiosis accentuated. In addition, in PrP22Lstripes, enhanced reactive astrocyte processes associated with microglia activation support interdependent events between the topographic pattern of Purkinje cell death, reactive gliosis and PrP22Laccumulation. Finally, we find that in preclinically-ill mice prion infection promotes at the membrane of astrocytes enveloping Purkinje cell excitatory synapses, upregulation of tumor necrosis factor-α receptor type 1 (TNFR1), a key mediator of the neuroinflammation process. These overall data show that Purkinje cell sensitivity to prion insult is locally restricted by the parasagittal compartmentation of the cerebellum, and that perisynaptic astrocytes may contribute to prion pathogenesis through prion-induced TNFR1 upregulation.
authors.affiliation: Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires & Intégratives, CNRS UPR 3212, Strasbourg, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Ragagnin
authors.affiliation: INSERM UMR-S1124, Cellules Souches, Signalisation et Prions, Université Paris Descartes, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Ezpeleta
authors.affiliation: Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires & Intégratives, CNRS UPR 3212, Strasbourg, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Guillemain
authors.affiliation: INSERM UMR-S1124, Cellules Souches, Signalisation et Prions, Université Paris Descartes, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Boudet-Devaud
authors.affiliation: Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires & Intégratives, CNRS UPR 3212, Strasbourg, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Haeberlé
authors.affiliation: Plateforme Imagerie In Vitro, CNRS UPS-3156, Université de Strasbourg, Strasbourg, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Demais
authors.affiliation: Institut Pasteur, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Vidal
authors.affiliation: Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires & Intégratives, CNRS UPR 3212, Strasbourg, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Demuth
authors.affiliation: VIM, INRA, Université Paris-Saclay, Jouy-en-Josas, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Béringue
authors.affiliation: INSERM UMR-S1124, Cellules Souches, Signalisation et Prions, Université Paris Descartes, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Kellermann
authors.affiliation: INSERM UMR-S1124, Cellules Souches, Signalisation et Prions, Université Paris Descartes, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Schneider
authors.affiliation: Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires & Intégratives, CNRS UPR 3212, Strasbourg, France.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Grant
authors.affiliation: Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires & Intégratives, CNRS UPR 3212, Strasbourg, France.
authors.forename: Yannick
authors.identifier: 0000-0002-2635-6385
authors.initials: Y
authors.lastname: Bailly
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology*; D016643:Encephalopathy, Bovine Spongiform / Q000378:metabolism / Q000473:pathology; D050581:Excitatory Amino Acid Transporter 4 / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000072002:Prion Proteins / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D012608:Scrapie / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000378:metabolism / Q000473:pathology
chemical_list: D050581:Excitatory Amino Acid Transporter 4; D000072002:Prion Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C493390:Slc1a6 protein, mouse; C506236:Tnfrsf1a protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: Purkinje cell; cerebellar compartmentation; inflammation; prion; zebrin