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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 recognition and spatial working memory impairment.(A) Performance in the novel object recognition task was expressed as a discrimination index (see Experimental Procedures). Histograms indicate the mean ± SEM of 10 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, and 8 Tg(FFI-26+/-)/Prnp0/0 aged 70 days; F2,25 = 8.3 p = 0.017 by one-way ANOVA; *p < 0.05, **p < 0.01, Tukey’s post hoc test. (B) Histograms represent the mean ± SEM of total errors in the eight-arm radial maze in the first eight trials during 16 days of training, by the same non-Tg/Prnp0/0 and Tg(FFI-26+/-)/Prnp0/0 mice used in A. t16 = 3.0; p = 0.009; **p < 0.01 by Student’s t test. (C) Values are the mean latency (± SEM) to complete the radial maze. F15,240 = 19; p = 0.03 by one-way ANOVA for repeated measures. *p < 0.05 by Student’s t test.
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ppat.1004796.g007: Tg(FFI) mice show recognition and spatial working memory impairment.(A) Performance in the novel object recognition task was expressed as a discrimination index (see Experimental Procedures). Histograms indicate the mean ± SEM of 10 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, and 8 Tg(FFI-26+/-)/Prnp0/0 aged 70 days; F2,25 = 8.3 p = 0.017 by one-way ANOVA; *p < 0.05, **p < 0.01, Tukey’s post hoc test. (B) Histograms represent the mean ± SEM of total errors in the eight-arm radial maze in the first eight trials during 16 days of training, by the same non-Tg/Prnp0/0 and Tg(FFI-26+/-)/Prnp0/0 mice used in A. t16 = 3.0; p = 0.009; **p < 0.01 by Student’s t test. (C) Values are the mean latency (± SEM) to complete the radial maze. F15,240 = 19; p = 0.03 by one-way ANOVA for repeated measures. *p < 0.05 by Student’s t test.

Mentions: We found alterations in long-term recognition and spatial working memory too in Tg(FFI) mice, tested in the novel object recognition task and eight-arm radial maze. To avoid confounding effects due to the motor deficit that develops in older mice, we tested Tg(FFI-26) animals younger than 100 days. Mice were impaired in long-term memory, as shown by the lower discrimination index in the object recognition task compared to non-Tg mice (Fig 7A). They also performed poorly in the eight-arm radial maze, which tests spatial working memory, making significantly more errors in the first eight training trials than controls (Fig 7B). Latency to complete the test was longer in Tg(FFI) than non-Tg mice (Fig 7C). This may reflect an impairment in choice-making, since there were no significant differences in the number of total movements in the open field (total line crossings: non-Tg = 304 ± 13; Tg(FFI-26) = 283 ± 23; mean ± SEM), confirming no motor deficit at this stage.


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 recognition and spatial working memory impairment.(A) Performance in the novel object recognition task was expressed as a discrimination index (see Experimental Procedures). Histograms indicate the mean ± SEM of 10 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, and 8 Tg(FFI-26+/-)/Prnp0/0 aged 70 days; F2,25 = 8.3 p = 0.017 by one-way ANOVA; *p < 0.05, **p < 0.01, Tukey’s post hoc test. (B) Histograms represent the mean ± SEM of total errors in the eight-arm radial maze in the first eight trials during 16 days of training, by the same non-Tg/Prnp0/0 and Tg(FFI-26+/-)/Prnp0/0 mice used in A. t16 = 3.0; p = 0.009; **p < 0.01 by Student’s t test. (C) Values are the mean latency (± SEM) to complete the radial maze. F15,240 = 19; p = 0.03 by one-way ANOVA for repeated measures. *p < 0.05 by Student’s t test.
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ppat.1004796.g007: Tg(FFI) mice show recognition and spatial working memory impairment.(A) Performance in the novel object recognition task was expressed as a discrimination index (see Experimental Procedures). Histograms indicate the mean ± SEM of 10 non-Tg/Prnp+/+, 10 non-Tg/Prnp0/0, and 8 Tg(FFI-26+/-)/Prnp0/0 aged 70 days; F2,25 = 8.3 p = 0.017 by one-way ANOVA; *p < 0.05, **p < 0.01, Tukey’s post hoc test. (B) Histograms represent the mean ± SEM of total errors in the eight-arm radial maze in the first eight trials during 16 days of training, by the same non-Tg/Prnp0/0 and Tg(FFI-26+/-)/Prnp0/0 mice used in A. t16 = 3.0; p = 0.009; **p < 0.01 by Student’s t test. (C) Values are the mean latency (± SEM) to complete the radial maze. F15,240 = 19; p = 0.03 by one-way ANOVA for repeated measures. *p < 0.05 by Student’s t test.
Mentions: We found alterations in long-term recognition and spatial working memory too in Tg(FFI) mice, tested in the novel object recognition task and eight-arm radial maze. To avoid confounding effects due to the motor deficit that develops in older mice, we tested Tg(FFI-26) animals younger than 100 days. Mice were impaired in long-term memory, as shown by the lower discrimination index in the object recognition task compared to non-Tg mice (Fig 7A). They also performed poorly in the eight-arm radial maze, which tests spatial working memory, making significantly more errors in the first eight training trials than controls (Fig 7B). Latency to complete the test was longer in Tg(FFI) than non-Tg mice (Fig 7C). This may reflect an impairment in choice-making, since there were no significant differences in the number of total movements in the open field (total line crossings: non-Tg = 304 ± 13; Tg(FFI-26) = 283 ± 23; mean ± SEM), confirming no motor deficit at this stage.

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