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ARS Home » Pacific West Area » Albany, California » Western Regional Research Center » Produce Safety and Microbiology Research » Research » Publications at this Location » Publication #326596

Title: Identification of new molecular alterations in Fatal Familial Insomnia.

item FERRER, ISIDRO - University Of Barcelona
item LLORENS, FRANC - University Of Gottingen
item FRAU-MENDEZ, MARGALIDA - University Of Barcelona
item FRNANDEZ-VEGA, IVAN - University Of Basque Country
item THUNE, KATRIN - University Of Basque Country
item DEL RIO, JOSE - University Of Barcelona
item SCHMITZ, MATTHIAS - University Of Gottingen
item ANSOLEAGA, BELEN - University Of Barcelona
item GOTZMANN, NADINE - University Of Gottingen
item CRAMM, MARIA - University Of Gottingen
item Silva, Christopher - Chris
item ZERR, INGA - University Of Gottingen
item ZARRANZ, JUAN JOSE - University Of Basque Country

Submitted to: Prion
Publication Type: Abstract Only
Publication Acceptance Date: 4/4/2016
Publication Date: 5/10/2016
Citation: Ferrer, I., Llorens, F., Frau-Mendez, M.A., Frnandez-Vega, I., Thune, K., Del Rio, J.A., Schmitz, M., Ansoleaga, B., Gotzmann, N., Cramm, M., Silva, C.J., Zerr, I., Zarranz, J. 2016. Identification of new molecular alterations in Fatal Familial Insomnia. Prion 10 (Supplement 1): S83.

Interpretive Summary: Prion diseases occur when a normal cellular prion protein becomes misfolded. The misfolded form can induce other normal cellular prion proteins to misfold, thereby propagating an infection. This work describes microscopic features of an uncommon prion disease, Fatal Familial Insomnia (FFI),that runs in families and is caused by a rare mutation of the normal cellular prion protein gene. When the brains of seven FFI patients were examined, some regions were consistently damaged by this disease while others were damaged to varying extents. The amount of the mutated form of the normal cellular prion protein (FFI-PrP) was found to be lower than would be expected in the FFI patients’ brains. In these brains, both the normal form of the FFI-PrP protein and the infectious form of the FFI-PrP protein (prion) showed differences in the amounts of attached sugars (glycosylation). The normal form of the FFI-PrP protein was also less soluble than would be expected. Again, only some areas of the brain had prions to amplify, using the RT-QuIC assay. The amounts of other proteins involved with energy production were uniformly reduced in the brains from FFI patients. In addition, proteins associated with packaging of DNA were noticeably reduced. In other parts of the brains from FFI patients, the amount of an antioxidant enzyme (superoxide dismutase 2) was markedly increased. These results provide evidence for the ways in which FFI disease damages cells at a molecular level.

Technical Abstract: Fatal familial insomnia (FFI) is an autosomal dominant prion disease caused by a D178N mutation in PRNP in combination with methionine (Met) at codon 129 in the mutated allele of the same gene (D178N-129M haplotype). The present study analyzes pathological and molecular features in seven FFI cases carrying the mutation D178N and Met/Met homozygous at the codon 129 of PRNP. Severe neuronal loss and marked astrocytic gliosis was observed in every case in the mediodorsal and anterior nuclei of the thalamus whereas the entorhinal cortex (EC) was variably affected. Spongiform degeneration was only observed in the EC. Synaptic and fine granular PrPSc immunoreactivity was found in the EC but not in thalamus. Microglia was barely increased in the mediodorsal thalamus, but mRNA expression of IL6, IL10RA, CSF3R and TLR7 was found in the thalamus in FFI. PrPC levels were significantly decreased in the thalamus, EC and cerebellum in FFI compared with controls. However, increased expression of the non-glycosylated band of about 19 kDa was observed in the thalamus when using PrP antibodies mapping to the central region of the PrP comprising the a-helix domains H1 and H2. Decreased PrP mRNA levels were also observed in the thalamus and EC. Altered PrP solubility was found in FFI compared with controls; significantly reduced PrP levels in the cytoplasmic fraction and increased insoluble levels were found in FFI cases when compared with controls. Amyloid-like deposits were only seen in the EC. RT-QuIC assay which mimics in vitro the conversion of PrPc to misfolded and amyloid PrP revealed that all the FFI samples of the entorhinal cortex were positive whereas the thalamus was positive only in three cases; the cerebellum was positive in two cases. All controls were negative. The expression of subunits of mitochondrial respiratory complexes and components of the protein synthesis machinery from the nucleolus to the ribosome was analyzed in the mediodorsal thalamus. NDUFB8 (complex I subunit), SDHB (complex II subunit), UQCRC2 (complex III subunit), COX2 (complex IV subunit) and ATP50 (complex V subunit) expression levels were reduced in FFI. Voltage-dependent anion channel and ATP5H were also reduced. In contrast, a marked increase in superoxide dismutase 2 was found in reactive astrocytes. The histone-binding chaperones nucleolin and nucleoplasmin 3, and histone H3 di-methylated K9 were markedly reduced together with a decrease in the expression of protein transcription elongation factor eEF1A in mediodorsal thalamus.