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@INPROCEEDINGS{LlorensTorres:150981,
      author       = {Llorens Torres, Francesc Josep and Thüne, Katrin and
                      Gotzmann, Nadine and Cramm, Maria},
      title        = {{I}dentification of new molecular alterations in {F}atal
                      {F}amilial {I}nsomnia},
      journal      = {Prion},
      volume       = {10},
      number       = {sup1},
      issn         = {1933-6896},
      reportid     = {DZNE-2020-01040},
      pages        = {S37-S127},
      year         = {2016},
      abstract     = {Fatal familial insomnia (FFI) is an autosomaldominant prion
                      disease caused by a D178Nmutation in PRNP in combination
                      with methio-nine at codon 129 in the mutated allele of
                      thesame gene. The present study analyzes patho-logical and
                      molecular features in 7 FFI casescarrying the mutation D178N
                      and M homozy-gous at the codon 129 of PRNP. Severe neuro-nal
                      loss and marked astrocytic gliosis wasobserved in every case
                      in the mediodorsal andanterior nuclei of the thalamus
                      whereas theentorhinal cortex (EC) was variably affected.
                      Spongiform degeneration was only observed inthe EC. Synaptic
                      and fine granular PrPScimmu-noreactivity was found in
                      theECbut not in thal-amus. Microglia was barely increased in
                      themediodorsal thalamus, but mRNA expressionof IL6, IL10RA,
                      CSF3R and TLR7 was foundin the thalamus in FFI. PrPClevels
                      were signifi-cantly decreased in the thalamus,ECand
                      cere-bellum in FFI compared with controls.However, increased
                      expression of the non-gly-cosylated band of about 19 kDa was
                      observedin the thalamus when using PrP antibodiesmapping to
                      the central region of the PrP com-prising thea-helix domains
                      H1 and H2.Decreased PrP mRNA levels were alsoobserved in the
                      thalamus andEC. Altered PrPsolubility was observed in FFI
                      compared withcontrols; significantly reduced PrP levels in
                      thecytoplasmic fraction and increased insolublelevels were
                      found in FFI cases when comparedwith controls. Amyloid-like
                      deposits were onlyseen in theEC. RT-QuIC assay which
                      mimicsinvitrothe conversion of PrPc to misfolded andamyloid
                      PrP revealed that all the FFI samplesof the entorhinal
                      cortex were positive whereasthe thalamus was positive only
                      in 3 cases; thecerebellum was positive in 2 cases. All
                      controlswere negative. The expression of subunits
                      ofmitochondrial respiratory complexes and com-ponents of the
                      protein synthesis machineryfrom the nucleolus to the
                      ribosome was ana-lyzed in the mediodorsal thalamus.
                      NDUFB8(complex I subunit), SDHB (complex II sub-unit),
                      UQCRC2 (complex III subunit), COX2(complex IV subunit) and
                      ATP50 (complex Vsubunit) expression levels were reduced in
                      FFI.Voltage-dependent anion channel and ATP5Hwere also
                      reduced. In contrast, a markedincrease in superoxide
                      dismutase 2 was foundin reactive astrocytes. The
                      histone-bindingchaperones nucleolin and nucleoplasmin 3,
                      andhistone H3 di-methylated K9 were markedlyreduced together
                      with a decrease in the expres-sion of protein transcription
                      elongation factoreEF1A in mediodorsal thalamus.},
      month         = {May},
      date          = {2016-05-10},
      organization  = {PRION 2016, Tokyo (Japan), 10 May 2016
                       - 13 May 2016},
      cin          = {AG Zerr},
      ddc          = {570},
      cid          = {I:(DE-2719)1440011-1},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      pubmed       = {pmid:27088811},
      doi          = {10.1080/19336896.2016.1162644},
      url          = {https://pub.dzne.de/record/150981},
}