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Title: Identification of new molecular alterations in Fatal Familial Insomnia

item LLORENS, FRANC - University Of Gottingen
item THUNE, KATRIN - University Of Gottingen
item SCHMITZ, MATTHIAS - University Of Gottingen
item CRAMM, MARIA - University Of Gottingen
item TAHIR, WAQAS - University Of Gottingen
item GOTZMANN, NADINE - University Of Gottingen
item ZERR, INGA - University Of Gottingen
item Silva, Christopher - Chris
item FRAU-MENDEZ, MARAGALIDA - University Of Barcelona
item ANSOLEAGA, BELEN - University Of Barcelona
item BERJAWI, SARA - University Of Barcelona
item CARMONA, MARGARITA - University Of Barcelona
item FERRAR, ISIDRO - University Of Barcelona
item FERNANDEZ, IVAN - University Of Basque Country
item ZARRANZ, JUAN JOSE - University Of Basque Country

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/1/2016
Publication Date: 4/7/2016
Citation: Llorens, F., Thune, K., Schmitz, M., Cramm, M., Tahir, W., Gotzmann, N., Zerr, I., Silva, C.J., Frau-Mendez, M.A., Ansoleaga, B., Berjawi, S., Carmona, M., Ferrar, I., Fernandez, I., Zarranz, J. 2016. Identification of new molecular alterations in Fatal Familial Insomnia. Human Molecular Genetics. Vol: 25; Page: 2417-2436.

Interpretive Summary: Fatal Familial Insomnia (FFI) is a rare prion disease that is caused by a mutation of the normal cellular prion protein gene. As its name implies, the disease runs in families and is characterized by profound changes in the sleep patterns of the patient. In addition patients also suffer from other neurological problems. This paper describes new disease characteristics and biochemical observations from a group of eight patients afflicted with the disease. Some regions of the brain were markedly damaged by this disease and others were damaged to different extents. In patient afflicted with FFI, 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). In addition, the normal form of the FFI-PrP protein was less soluble than would be expected. The RT-QuIC assay was used to amplify the prions in the patients’ brain, but only some areas of the brain had prions to amplify. These findings show the particular characteristics of natural FFI-PrP and the FFI-PrP prion.

Technical Abstract: Fatal Familial Insomnia (FFI) 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, hallucinations, delirium, and spontaneous and evoked myoclonus, among other symptoms. The present 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 (EC) is variably affected. Spongiform degeneration only occurs in the EC. Synaptic and fine granular PrPSc immunoreactivity is found in the EC but not in the thalamus. IL6, IL10RA, CSF3R and TLR7 mRNA expression increases in the thalamus in FFI. mRNA and PrPC protein levels are significantly decreased in the thalamus, EC and cerebellum in FFI. This is accompanied by a particular PrPC and PrPres band profile with over-representation of the diglycosylated band and under-expression of the nonglycosylated band. 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 when compared with controls. Amyloid-like deposits are only seen in the EC. The RT-QuIC assay, which mimics in vitro the conversion of PrPC to misfolded and amyloid PrP, 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. All controls were negative. These findings show particular characteristics of natural prion protein in FFI, altered PrPres and PrPSc patterns and region-dependent putative capacity of PrP seeding in FFI.