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

Tg(FFI) mice develop motor dysfunction which is not rescued by co-expression of wild-type PrP.(A) Groups of 7–12 Tg(FFI-26+/-)/Prnp0/0 and 9–13 non-Tg/Prnp0/0 littermates were tested on a Rotarod at the ages indicated. Each mouse was tested three times, and the mean latency to fall was calculated. Bars indicate the mean ± SEM of latency to fall (s); F10,192 = 10.82, p < 0.0001 by two-way ANOVA; **p < 0.01 and ****p < 0.0001 Šidàk’s post hoc test. (B) Groups of 6–19 (240–450 days old) and 10–11 (600–700 days old) Tg(FFI-10+/-)/Prnp0/0, Tg(FFI-10+/+)/Prnp0/0 and non-Tg/Prnp0/0 littermates were tested on a Rotarod. Bars indicate the mean ± SEM of latency to fall (s); F2,28 = 34.05, p < 0.0001 by one-way ANOVA; *p < 0.05 and ****p < 0.0001 vs. non-Tg; Tukey’s post hoc test. (C) Groups of 9 Tg(FFI-26+/-)/Prnp0/0, 10 Tg(FFI-26+/-)/Prnp+/0, and 8 Tg(FFI-26+/-)/Prnp+/+ littermates were tested on a Rotarod and the ages indicated. F2,45 = 0.3374; p = 0.7154 by two-way ANOVA.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004796.g006: Tg(FFI) mice develop motor dysfunction which is not rescued by co-expression of wild-type PrP.(A) Groups of 7–12 Tg(FFI-26+/-)/Prnp0/0 and 9–13 non-Tg/Prnp0/0 littermates were tested on a Rotarod at the ages indicated. Each mouse was tested three times, and the mean latency to fall was calculated. Bars indicate the mean ± SEM of latency to fall (s); F10,192 = 10.82, p < 0.0001 by two-way ANOVA; **p < 0.01 and ****p < 0.0001 Šidàk’s post hoc test. (B) Groups of 6–19 (240–450 days old) and 10–11 (600–700 days old) Tg(FFI-10+/-)/Prnp0/0, Tg(FFI-10+/+)/Prnp0/0 and non-Tg/Prnp0/0 littermates were tested on a Rotarod. Bars indicate the mean ± SEM of latency to fall (s); F2,28 = 34.05, p < 0.0001 by one-way ANOVA; *p < 0.05 and ****p < 0.0001 vs. non-Tg; Tukey’s post hoc test. (C) Groups of 9 Tg(FFI-26+/-)/Prnp0/0, 10 Tg(FFI-26+/-)/Prnp+/0, and 8 Tg(FFI-26+/-)/Prnp+/+ littermates were tested on a Rotarod and the ages indicated. F2,45 = 0.3374; p = 0.7154 by two-way ANOVA.

Mentions: To check the earliest appearance of motor dysfunction, Tg(FFI-26) mice were tested on the accelerating Rotarod. They performed well until 90 days of age, indicating normal development of motor function. From 110 days on, however, the mutant mice showed a significantly shorter latency to fall than nontransgenic littermates; their performance worsened with aging until they became unable to stay on the rod (Fig 6A).


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 develop motor dysfunction which is not rescued by co-expression of wild-type PrP.(A) Groups of 7–12 Tg(FFI-26+/-)/Prnp0/0 and 9–13 non-Tg/Prnp0/0 littermates were tested on a Rotarod at the ages indicated. Each mouse was tested three times, and the mean latency to fall was calculated. Bars indicate the mean ± SEM of latency to fall (s); F10,192 = 10.82, p < 0.0001 by two-way ANOVA; **p < 0.01 and ****p < 0.0001 Šidàk’s post hoc test. (B) Groups of 6–19 (240–450 days old) and 10–11 (600–700 days old) Tg(FFI-10+/-)/Prnp0/0, Tg(FFI-10+/+)/Prnp0/0 and non-Tg/Prnp0/0 littermates were tested on a Rotarod. Bars indicate the mean ± SEM of latency to fall (s); F2,28 = 34.05, p < 0.0001 by one-way ANOVA; *p < 0.05 and ****p < 0.0001 vs. non-Tg; Tukey’s post hoc test. (C) Groups of 9 Tg(FFI-26+/-)/Prnp0/0, 10 Tg(FFI-26+/-)/Prnp+/0, and 8 Tg(FFI-26+/-)/Prnp+/+ littermates were tested on a Rotarod and the ages indicated. F2,45 = 0.3374; p = 0.7154 by two-way ANOVA.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004796.g006: Tg(FFI) mice develop motor dysfunction which is not rescued by co-expression of wild-type PrP.(A) Groups of 7–12 Tg(FFI-26+/-)/Prnp0/0 and 9–13 non-Tg/Prnp0/0 littermates were tested on a Rotarod at the ages indicated. Each mouse was tested three times, and the mean latency to fall was calculated. Bars indicate the mean ± SEM of latency to fall (s); F10,192 = 10.82, p < 0.0001 by two-way ANOVA; **p < 0.01 and ****p < 0.0001 Šidàk’s post hoc test. (B) Groups of 6–19 (240–450 days old) and 10–11 (600–700 days old) Tg(FFI-10+/-)/Prnp0/0, Tg(FFI-10+/+)/Prnp0/0 and non-Tg/Prnp0/0 littermates were tested on a Rotarod. Bars indicate the mean ± SEM of latency to fall (s); F2,28 = 34.05, p < 0.0001 by one-way ANOVA; *p < 0.05 and ****p < 0.0001 vs. non-Tg; Tukey’s post hoc test. (C) Groups of 9 Tg(FFI-26+/-)/Prnp0/0, 10 Tg(FFI-26+/-)/Prnp+/0, and 8 Tg(FFI-26+/-)/Prnp+/+ littermates were tested on a Rotarod and the ages indicated. F2,45 = 0.3374; p = 0.7154 by two-way ANOVA.
Mentions: To check the earliest appearance of motor dysfunction, Tg(FFI-26) mice were tested on the accelerating Rotarod. They performed well until 90 days of age, indicating normal development of motor function. From 110 days on, however, the mutant mice showed a significantly shorter latency to fall than nontransgenic littermates; their performance worsened with aging until they became unable to stay on the rod (Fig 6A).

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