title: Identification of new molecular alterations in fatal familial insomnia.
abstract: Fatal familial insomnia is a rare disease caused by a D178N mutation in combination with methionine (Met) at codon 129 in the mutated allele of PRNP (D178N-129M haplotype). FFI is manifested by sleep disturbances with insomnia, autonomic disorders and spontaneous and evoked myoclonus, among other symptoms. This study describes new neuropathological and biochemical observations in a series of eight patients with FFI. The mediodorsal and anterior nuclei of the thalamus have severe neuronal loss and marked astrocytic gliosis in every case, whereas the entorhinal cortex is variably affected. Spongiform degeneration only occurs in the entorhinal cortex. Synaptic and fine granular proteinase K digestion (PrPres) immunoreactivity is found in the entorhinal cortex but not in the thalamus. Interleukin 6, interleukin 10 receptor alpha subunit, colony stimulating factor 3 receptor and toll-like receptor 7 mRNA expression increases in the thalamus in FFI. PrPc levels are significantly decreased in the thalamus, entorhinal cortex and cerebellum in FFI. This is accompanied by a particular PrPc and PrPres band profile. Altered PrP solubility consistent with significantly reduced PrP levels in the cytoplasmic fraction and increased PrP levels in the insoluble fraction are identified in FFI cases. Amyloid-like deposits are only seen in the entorhinal cortex. The RT-QuIC assay reveals that all the FFI samples of the entorhinal cortex are positive, whereas the thalamus is positive only in three cases and the cerebellum in two cases. The present findings unveil particular neuropathological and neuroinflammatory profiles in FFI and novel characteristics of natural prion protein in FFI, altered PrPres and Scrapie PrP (abnormal and pathogenic PrP) patterns and region-dependent putative capacity of PrP seeding.
authors.affiliation: Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen 37075, Germany.
authors.forename: Franc
authors.initials: F
authors.lastname: Llorens
authors.affiliation: Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen 37075, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Thüne
authors.affiliation: Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen 37075, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmitz
authors.affiliation: Institute of Neuropathology, Service of Pathological Anatomy, Bellvitge University Hospital, University of Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, and Biomedical Research Center of Neurodegenerative Diseases (CIBERNED) Hospitalet del Llobregat 08907, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Ansoleaga
authors.affiliation: Institute of Neuropathology, Service of Pathological Anatomy, Bellvitge University Hospital, University of Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, and Biomedical Research Center of Neurodegenerative Diseases (CIBERNED) Hospitalet del Llobregat 08907, Spain.
authors.forename: Margalida A
authors.initials: MA
authors.lastname: Frau-Méndez
authors.affiliation: Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen 37075, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Cramm
authors.affiliation: Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen 37075, Germany.
authors.forename: Waqas
authors.initials: W
authors.lastname: Tahir
authors.affiliation: Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen 37075, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Gotzmann
authors.affiliation: Institute of Neuropathology, Service of Pathological Anatomy, Bellvitge University Hospital, University of Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, and Biomedical Research Center of Neurodegenerative Diseases (CIBERNED) Hospitalet del Llobregat 08907, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Berjaoui
authors.affiliation: Institute of Neuropathology, Service of Pathological Anatomy, Bellvitge University Hospital, University of Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, and Biomedical Research Center of Neurodegenerative Diseases (CIBERNED) Hospitalet del Llobregat 08907, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Carmona
authors.affiliation: USDA, Produce Safety & Microbiology Research Unit, Western Regional Research Center, Albany, CA 94710, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Silva
authors.affiliation: Pathology Department University Hospital Araba, and Brain Bank Araba University Hospital, Basque Biobank for Research (O+eHun), Alava 01009, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Fernandez-Vega
authors.affiliation: Neurology Department, University Hospital Cruces, University of the Basque Country, Bizkaia 48903, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: José Zarranz
authors.affiliation: Department of Neurology, University Medical Center Göttingen, and German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen 37075, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
authors.affiliation: Institute of Neuropathology, Service of Pathological Anatomy, Bellvitge University Hospital, University of Barcelona, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, and Biomedical Research Center of Neurodegenerative Diseases (CIBERNED) Hospitalet del Llobregat 08907, Spain 8082ifa@gmail.com.
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D018728:Entorhinal Cortex / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005911:Gliosis / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D034062:Insomnia, Fatal Familial / Q000235:genetics* / Q000503:physiopathology; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D017096:Prion Diseases / Q000235:genetics* / Q000503:physiopathology; D000072002:Prion Proteins / Q000235:genetics*; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics*; D013788:Thalamus / Q000378:metabolism / Q000503:physiopathology; D051199:Toll-Like Receptor 7 / Q000235:genetics*
chemical_list: C517047:CSF3R protein, human; D053709:Interleukin-10 Receptor alpha Subunit; D015850:Interleukin-6; C512656:PRNP protein, human; D000072002:Prion Proteins; D016184:Receptors, Colony-Stimulating Factor; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7