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| Home > Publications Database > Identification of new molecular alterations in Fatal Familial Insomnia |
| Home > Publications Database > Identification of new molecular alterations in Fatal Familial Insomnia |
| Abstract/Journal Article | DZNE-2020-01040 |
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2016
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Please use a persistent id in citations: doi:10.1080/19336896.2016.1162644
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.
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