Limits...
Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.

Bouybayoune I, Mantovani S, Del Gallo F, Bertani I, Restelli E, Comerio L, Tapella L, Baracchi F, Fernández-Borges N, Mangieri M, Bisighini C, Beznoussenko GV, Paladini A, Balducci C, Micotti E, Forloni G, Castilla J, Fiordaliso F, Tagliavini F, Imeri L, Chiesa R - PLoS Pathog. (2015)

Bottom Line: However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known.No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation.Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.

ABSTRACT
Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

No MeSH data available.


Related in: MedlinePlus

Amount of sleep and EEG delta power during NREM sleep.Values are the mean ± SEM of 8 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, 8 Tg(FFI-26)/Prnp+/0 and 9 Tg(FFI-26)/Prnp0/0 mice. The grey areas indicate the dark portion of the light-dark cycle. *,°p ≤ 0.05; **,°°p ≤ 0.01. A mixed model for repeated measures was used. Between-strain comparisons (*) were done by one-way ANOVA with Bonferroni's correction. Within-condition comparisons (°) were done by paired Student's t test.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4400166&req=5

ppat.1004796.g004: Amount of sleep and EEG delta power during NREM sleep.Values are the mean ± SEM of 8 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, 8 Tg(FFI-26)/Prnp+/0 and 9 Tg(FFI-26)/Prnp0/0 mice. The grey areas indicate the dark portion of the light-dark cycle. *,°p ≤ 0.05; **,°°p ≤ 0.01. A mixed model for repeated measures was used. Between-strain comparisons (*) were done by one-way ANOVA with Bonferroni's correction. Within-condition comparisons (°) were done by paired Student's t test.

Mentions: Slow-wave activity (SWA) during NREM sleep (a measure of sleep drive and depth [17]) and EEG spindles (which characterize this sleep phase) were reduced in Tg(FFI)/Prnp0/0 mice. Although the amount of NREM sleep was not reduced in Tg(FFI)/Prnp0/0 mice in comparison to the other mice, NREM sleep SWA was significantly less in Tg(FFI)/Prnp0/0 mice than in both non-Tg/Prnp+/+ and non-Tg/Prnp0/0 mice during the first portion of the light phase (Fig 4). The density of EEG spindles during NREM sleep in the light phase was lower in Tg(FFI)/Prnp0/0 mice (38.4 ± 7.5 spindles/h) than in both non-Tg/Prnp+/+ and non-Tg/Prnp0/0 mice (184.4 ± 11.0 and 148.0 ± 9.1 spindles/h, respectively; p < 0.01 by one-way ANOVA F3.31 = 35.587). The density of spindles in Tg(FFI)/Prnp+/0 mice (106.8 ± 14.3 spindles/h) was intermediate between that of non-Tg/Prnp+/+ and Tg(FFI)/Prnp0/0 mice, and significantly different from both.


Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.

Bouybayoune I, Mantovani S, Del Gallo F, Bertani I, Restelli E, Comerio L, Tapella L, Baracchi F, Fernández-Borges N, Mangieri M, Bisighini C, Beznoussenko GV, Paladini A, Balducci C, Micotti E, Forloni G, Castilla J, Fiordaliso F, Tagliavini F, Imeri L, Chiesa R - PLoS Pathog. (2015)

Amount of sleep and EEG delta power during NREM sleep.Values are the mean ± SEM of 8 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, 8 Tg(FFI-26)/Prnp+/0 and 9 Tg(FFI-26)/Prnp0/0 mice. The grey areas indicate the dark portion of the light-dark cycle. *,°p ≤ 0.05; **,°°p ≤ 0.01. A mixed model for repeated measures was used. Between-strain comparisons (*) were done by one-way ANOVA with Bonferroni's correction. Within-condition comparisons (°) were done by paired Student's t test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400166&req=5

ppat.1004796.g004: Amount of sleep and EEG delta power during NREM sleep.Values are the mean ± SEM of 8 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, 8 Tg(FFI-26)/Prnp+/0 and 9 Tg(FFI-26)/Prnp0/0 mice. The grey areas indicate the dark portion of the light-dark cycle. *,°p ≤ 0.05; **,°°p ≤ 0.01. A mixed model for repeated measures was used. Between-strain comparisons (*) were done by one-way ANOVA with Bonferroni's correction. Within-condition comparisons (°) were done by paired Student's t test.
Mentions: Slow-wave activity (SWA) during NREM sleep (a measure of sleep drive and depth [17]) and EEG spindles (which characterize this sleep phase) were reduced in Tg(FFI)/Prnp0/0 mice. Although the amount of NREM sleep was not reduced in Tg(FFI)/Prnp0/0 mice in comparison to the other mice, NREM sleep SWA was significantly less in Tg(FFI)/Prnp0/0 mice than in both non-Tg/Prnp+/+ and non-Tg/Prnp0/0 mice during the first portion of the light phase (Fig 4). The density of EEG spindles during NREM sleep in the light phase was lower in Tg(FFI)/Prnp0/0 mice (38.4 ± 7.5 spindles/h) than in both non-Tg/Prnp+/+ and non-Tg/Prnp0/0 mice (184.4 ± 11.0 and 148.0 ± 9.1 spindles/h, respectively; p < 0.01 by one-way ANOVA F3.31 = 35.587). The density of spindles in Tg(FFI)/Prnp+/0 mice (106.8 ± 14.3 spindles/h) was intermediate between that of non-Tg/Prnp+/+ and Tg(FFI)/Prnp0/0 mice, and significantly different from both.

Bottom Line: However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known.No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation.Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, IRCCS-"Mario Negri" Institute for Pharmacological Research, Milan, Italy.

ABSTRACT
Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

No MeSH data available.


Related in: MedlinePlus