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 show thalamic and cerebellar atrophy.(A) Brain anatomy of a non-Tg/Prnp0/0 and a Tg(FFI-26+/-)/Prnp0/0 mouse aged 460 days. Representative T2-weighted images (TE/TR = 50/2500 ms). (B) Volumes of individual brains areas of 9 Tg(FFI-26+/-)/Prnp0/0 and 9 non-Tg/Prnp0/0 littermates aged between 408 and 498 days were quantified as described in the Experimental Procedures. To reduce interindividual variation, volumes were normalized on the values of the striatum which were the same in non-Tg and Tg(FFI) mice (non-Tg: 20.83 ± 0.30 mm3, Tg(FFI): 20.09 ± 0.32 mm3; mean ± SEM, p = 0.22 by Mann Whitney test). *p < 0.05 and **p < 0.01 vs. non-Tg by Mann Whitney test.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004796.g008: Tg(FFI) mice show thalamic and cerebellar atrophy.(A) Brain anatomy of a non-Tg/Prnp0/0 and a Tg(FFI-26+/-)/Prnp0/0 mouse aged 460 days. Representative T2-weighted images (TE/TR = 50/2500 ms). (B) Volumes of individual brains areas of 9 Tg(FFI-26+/-)/Prnp0/0 and 9 non-Tg/Prnp0/0 littermates aged between 408 and 498 days were quantified as described in the Experimental Procedures. To reduce interindividual variation, volumes were normalized on the values of the striatum which were the same in non-Tg and Tg(FFI) mice (non-Tg: 20.83 ± 0.30 mm3, Tg(FFI): 20.09 ± 0.32 mm3; mean ± SEM, p = 0.22 by Mann Whitney test). *p < 0.05 and **p < 0.01 vs. non-Tg by Mann Whitney test.

Mentions: We used magnetic resonance imaging (MRI) to investigate the effects of the FFI mutation on brain structure. There were no significant differences between the whole-brain volumes of Tg(FFI-26) and non-Tg littermates at 80 days of age (non-Tg = 464 ± 6 mm3; Tg(FFI-26) = 451 ± 5 mm3; mean ± SEM, n = 5–6; p = 0.0823 by Mann-Whitney test). In Tg(FFI-26) mice older than 400 days, the whole-brain volume was 12% smaller than controls (non-Tg = 493 ± 4 mm3; Tg(FFI-26) = 436 ± 6 mm3; mean ± SEM, n = 9; p < 0.0001 by Mann-Whitney test). Analysis of individual brain areas showed that the thalamic and cerebellar volumes were significantly smaller in Tg(FFI-26) mice than in non-Tg littermates, but there were no differences in the other brain regions (Fig 8).


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 thalamic and cerebellar atrophy.(A) Brain anatomy of a non-Tg/Prnp0/0 and a Tg(FFI-26+/-)/Prnp0/0 mouse aged 460 days. Representative T2-weighted images (TE/TR = 50/2500 ms). (B) Volumes of individual brains areas of 9 Tg(FFI-26+/-)/Prnp0/0 and 9 non-Tg/Prnp0/0 littermates aged between 408 and 498 days were quantified as described in the Experimental Procedures. To reduce interindividual variation, volumes were normalized on the values of the striatum which were the same in non-Tg and Tg(FFI) mice (non-Tg: 20.83 ± 0.30 mm3, Tg(FFI): 20.09 ± 0.32 mm3; mean ± SEM, p = 0.22 by Mann Whitney test). *p < 0.05 and **p < 0.01 vs. non-Tg by Mann Whitney test.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004796.g008: Tg(FFI) mice show thalamic and cerebellar atrophy.(A) Brain anatomy of a non-Tg/Prnp0/0 and a Tg(FFI-26+/-)/Prnp0/0 mouse aged 460 days. Representative T2-weighted images (TE/TR = 50/2500 ms). (B) Volumes of individual brains areas of 9 Tg(FFI-26+/-)/Prnp0/0 and 9 non-Tg/Prnp0/0 littermates aged between 408 and 498 days were quantified as described in the Experimental Procedures. To reduce interindividual variation, volumes were normalized on the values of the striatum which were the same in non-Tg and Tg(FFI) mice (non-Tg: 20.83 ± 0.30 mm3, Tg(FFI): 20.09 ± 0.32 mm3; mean ± SEM, p = 0.22 by Mann Whitney test). *p < 0.05 and **p < 0.01 vs. non-Tg by Mann Whitney test.
Mentions: We used magnetic resonance imaging (MRI) to investigate the effects of the FFI mutation on brain structure. There were no significant differences between the whole-brain volumes of Tg(FFI-26) and non-Tg littermates at 80 days of age (non-Tg = 464 ± 6 mm3; Tg(FFI-26) = 451 ± 5 mm3; mean ± SEM, n = 5–6; p = 0.0823 by Mann-Whitney test). In Tg(FFI-26) mice older than 400 days, the whole-brain volume was 12% smaller than controls (non-Tg = 493 ± 4 mm3; Tg(FFI-26) = 436 ± 6 mm3; mean ± SEM, n = 9; p < 0.0001 by Mann-Whitney test). Analysis of individual brain areas showed that the thalamic and cerebellar volumes were significantly smaller in Tg(FFI-26) mice than in non-Tg littermates, but there were no differences in the other brain regions (Fig 8).

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