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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

Tg(FFI) mice show an altered response to sleep deprivation.Time course of the loss and recovery of time spent in rapid eye movement (REM) (A) and non-rapid eye movement (NREM) (B) sleep, during and after sleep deprivation. Values were from 8 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, 9 Tg(FFI-26)/Prnp0/0 and 8 Tg(FFI-26)/Prnp+/0. Mice were kept awake during the first 6 h of the light phase (crosshatched bar) by gentle handling, and allowed to sleep freely in the next 18 h. The black bar indicates the dark portion of the light-dark cycle. REM and NREM sleep were calculated hourly for each animal as the difference between the amount of time spent in a given state (REM or NREM sleep) during and after sleep deprivation, and the amount spent in the corresponding hour during baseline conditions (undisturbed). The hour-by-hour differences were then summed to obtain a cumulative curve. Data (means ± SEM) are presented in 2-h intervals. Single symbols: p < 0.05; double symbols: p < 0.01. *, Tg(FFI-26)/Prnp0/0 vs non-Tg/Prnp0/0; °, Tg(FFI-26)/Prnp0/0 vs. non-Tg/Prnp+/+; §, Tg(FFI-26)/Prnp0/0 vs. Tg(FFI-26)/Prnp+/0; #, Tg(FFI-26)/Prnp+/0 vs. non-Tg/Prnp+/+. A mixed model analysis of variance for repeated measures was done on 6 h blocks. Between-strains post-hoc comparisons by one-way ANOVA with Bonferroni correction: (panel A) 0–6 h: F3,101 = 4.98, p = 0.003; 7–12 h: F3,101 = 5.25, p = 0.002; 13–18 h: F3,101 = 2.88, p = 0.05; 19–24 h: F3,101 = 3.30, p = 0.023. (panel B) 0–6 h: F3,101 = 1.01, p = 0.391; 7–12 h: F3,101 = 1.78, p = 0.156; 13–18 h: F3,101 = 3.76, p = 0.013; 19–24 h: F3,101 = 3.97, p = 0.010.
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ppat.1004796.g005: Tg(FFI) mice show an altered response to sleep deprivation.Time course of the loss and recovery of time spent in rapid eye movement (REM) (A) and non-rapid eye movement (NREM) (B) sleep, during and after sleep deprivation. Values were from 8 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, 9 Tg(FFI-26)/Prnp0/0 and 8 Tg(FFI-26)/Prnp+/0. Mice were kept awake during the first 6 h of the light phase (crosshatched bar) by gentle handling, and allowed to sleep freely in the next 18 h. The black bar indicates the dark portion of the light-dark cycle. REM and NREM sleep were calculated hourly for each animal as the difference between the amount of time spent in a given state (REM or NREM sleep) during and after sleep deprivation, and the amount spent in the corresponding hour during baseline conditions (undisturbed). The hour-by-hour differences were then summed to obtain a cumulative curve. Data (means ± SEM) are presented in 2-h intervals. Single symbols: p < 0.05; double symbols: p < 0.01. *, Tg(FFI-26)/Prnp0/0 vs non-Tg/Prnp0/0; °, Tg(FFI-26)/Prnp0/0 vs. non-Tg/Prnp+/+; §, Tg(FFI-26)/Prnp0/0 vs. Tg(FFI-26)/Prnp+/0; #, Tg(FFI-26)/Prnp+/0 vs. non-Tg/Prnp+/+. A mixed model analysis of variance for repeated measures was done on 6 h blocks. Between-strains post-hoc comparisons by one-way ANOVA with Bonferroni correction: (panel A) 0–6 h: F3,101 = 4.98, p = 0.003; 7–12 h: F3,101 = 5.25, p = 0.002; 13–18 h: F3,101 = 2.88, p = 0.05; 19–24 h: F3,101 = 3.30, p = 0.023. (panel B) 0–6 h: F3,101 = 1.01, p = 0.391; 7–12 h: F3,101 = 1.78, p = 0.156; 13–18 h: F3,101 = 3.76, p = 0.013; 19–24 h: F3,101 = 3.97, p = 0.010.

Mentions: Since additional alterations may become apparent when the sleep drive is increased, we investigated the response to sleep deprivation. Mice were kept awake during the first 6 h of the light phase by gentle handling, then allowed to sleep freely in the following 18 h. REM and NREM sleep, shown in Fig 5, was calculated hourly for each animal as the difference between the time spent in REM or NREM sleep during and after sleep deprivation, and the amount spent in the corresponding hour during baseline conditions (undisturbed). The hour-by-hour differences were then summed to give a cumulative curve.


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)

Tg(FFI) mice show an altered response to sleep deprivation.Time course of the loss and recovery of time spent in rapid eye movement (REM) (A) and non-rapid eye movement (NREM) (B) sleep, during and after sleep deprivation. Values were from 8 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, 9 Tg(FFI-26)/Prnp0/0 and 8 Tg(FFI-26)/Prnp+/0. Mice were kept awake during the first 6 h of the light phase (crosshatched bar) by gentle handling, and allowed to sleep freely in the next 18 h. The black bar indicates the dark portion of the light-dark cycle. REM and NREM sleep were calculated hourly for each animal as the difference between the amount of time spent in a given state (REM or NREM sleep) during and after sleep deprivation, and the amount spent in the corresponding hour during baseline conditions (undisturbed). The hour-by-hour differences were then summed to obtain a cumulative curve. Data (means ± SEM) are presented in 2-h intervals. Single symbols: p < 0.05; double symbols: p < 0.01. *, Tg(FFI-26)/Prnp0/0 vs non-Tg/Prnp0/0; °, Tg(FFI-26)/Prnp0/0 vs. non-Tg/Prnp+/+; §, Tg(FFI-26)/Prnp0/0 vs. Tg(FFI-26)/Prnp+/0; #, Tg(FFI-26)/Prnp+/0 vs. non-Tg/Prnp+/+. A mixed model analysis of variance for repeated measures was done on 6 h blocks. Between-strains post-hoc comparisons by one-way ANOVA with Bonferroni correction: (panel A) 0–6 h: F3,101 = 4.98, p = 0.003; 7–12 h: F3,101 = 5.25, p = 0.002; 13–18 h: F3,101 = 2.88, p = 0.05; 19–24 h: F3,101 = 3.30, p = 0.023. (panel B) 0–6 h: F3,101 = 1.01, p = 0.391; 7–12 h: F3,101 = 1.78, p = 0.156; 13–18 h: F3,101 = 3.76, p = 0.013; 19–24 h: F3,101 = 3.97, p = 0.010.
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ppat.1004796.g005: Tg(FFI) mice show an altered response to sleep deprivation.Time course of the loss and recovery of time spent in rapid eye movement (REM) (A) and non-rapid eye movement (NREM) (B) sleep, during and after sleep deprivation. Values were from 8 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, 9 Tg(FFI-26)/Prnp0/0 and 8 Tg(FFI-26)/Prnp+/0. Mice were kept awake during the first 6 h of the light phase (crosshatched bar) by gentle handling, and allowed to sleep freely in the next 18 h. The black bar indicates the dark portion of the light-dark cycle. REM and NREM sleep were calculated hourly for each animal as the difference between the amount of time spent in a given state (REM or NREM sleep) during and after sleep deprivation, and the amount spent in the corresponding hour during baseline conditions (undisturbed). The hour-by-hour differences were then summed to obtain a cumulative curve. Data (means ± SEM) are presented in 2-h intervals. Single symbols: p < 0.05; double symbols: p < 0.01. *, Tg(FFI-26)/Prnp0/0 vs non-Tg/Prnp0/0; °, Tg(FFI-26)/Prnp0/0 vs. non-Tg/Prnp+/+; §, Tg(FFI-26)/Prnp0/0 vs. Tg(FFI-26)/Prnp+/0; #, Tg(FFI-26)/Prnp+/0 vs. non-Tg/Prnp+/+. A mixed model analysis of variance for repeated measures was done on 6 h blocks. Between-strains post-hoc comparisons by one-way ANOVA with Bonferroni correction: (panel A) 0–6 h: F3,101 = 4.98, p = 0.003; 7–12 h: F3,101 = 5.25, p = 0.002; 13–18 h: F3,101 = 2.88, p = 0.05; 19–24 h: F3,101 = 3.30, p = 0.023. (panel B) 0–6 h: F3,101 = 1.01, p = 0.391; 7–12 h: F3,101 = 1.78, p = 0.156; 13–18 h: F3,101 = 3.76, p = 0.013; 19–24 h: F3,101 = 3.97, p = 0.010.
Mentions: Since additional alterations may become apparent when the sleep drive is increased, we investigated the response to sleep deprivation. Mice were kept awake during the first 6 h of the light phase by gentle handling, then allowed to sleep freely in the following 18 h. REM and NREM sleep, shown in Fig 5, was calculated hourly for each animal as the difference between the time spent in REM or NREM sleep during and after sleep deprivation, and the amount spent in the corresponding hour during baseline conditions (undisturbed). The hour-by-hour differences were then summed to give a cumulative curve.

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