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

Entry in REM sleep is abnormal in Tg(FFI) mice.Whereas a Tg(FFI-26)/Prnp0/0 mouse (A) enters REM sleep directly from wakefulness (left arrow), as shown by the hypnogram (lower trace), in a non-Tg/Prnp+/+ mouse REM sleep is preceded by an episode of NREM sleep (B). Top to bottom: EEG (electroencephalogram), EEG power in the delta (0.5–4 Hz, black line) and theta (6–9 Hz, red line) bands, and the related hypnogram. Arrows indicate the beginning and end of a REM sleep phase.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004796.g003: Entry in REM sleep is abnormal in Tg(FFI) mice.Whereas a Tg(FFI-26)/Prnp0/0 mouse (A) enters REM sleep directly from wakefulness (left arrow), as shown by the hypnogram (lower trace), in a non-Tg/Prnp+/+ mouse REM sleep is preceded by an episode of NREM sleep (B). Top to bottom: EEG (electroencephalogram), EEG power in the delta (0.5–4 Hz, black line) and theta (6–9 Hz, red line) bands, and the related hypnogram. Arrows indicate the beginning and end of a REM sleep phase.

Mentions: In 8 out of 9 Tg(FFI)/Prnp0/0 mice, entry into REM sleep was abnormal. Tg(FFI)/Prnp0/0 mice entered REM sleep directly from wakefulness in 24.6 ± 6.5% of REM epochs, instead of going through NREM sleep, as normally occurs (Fig 3). This was never observed in the other groups of mice.


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)

Entry in REM sleep is abnormal in Tg(FFI) mice.Whereas a Tg(FFI-26)/Prnp0/0 mouse (A) enters REM sleep directly from wakefulness (left arrow), as shown by the hypnogram (lower trace), in a non-Tg/Prnp+/+ mouse REM sleep is preceded by an episode of NREM sleep (B). Top to bottom: EEG (electroencephalogram), EEG power in the delta (0.5–4 Hz, black line) and theta (6–9 Hz, red line) bands, and the related hypnogram. Arrows indicate the beginning and end of a REM sleep phase.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1004796.g003: Entry in REM sleep is abnormal in Tg(FFI) mice.Whereas a Tg(FFI-26)/Prnp0/0 mouse (A) enters REM sleep directly from wakefulness (left arrow), as shown by the hypnogram (lower trace), in a non-Tg/Prnp+/+ mouse REM sleep is preceded by an episode of NREM sleep (B). Top to bottom: EEG (electroencephalogram), EEG power in the delta (0.5–4 Hz, black line) and theta (6–9 Hz, red line) bands, and the related hypnogram. Arrows indicate the beginning and end of a REM sleep phase.
Mentions: In 8 out of 9 Tg(FFI)/Prnp0/0 mice, entry into REM sleep was abnormal. Tg(FFI)/Prnp0/0 mice entered REM sleep directly from wakefulness in 24.6 ± 6.5% of REM epochs, instead of going through NREM sleep, as normally occurs (Fig 3). This was never observed in the other groups of mice.

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