Increased sensitivity to seizures in mice lacking cellular prion protein.
Roger Walz,Olavo B. Amaral,Isabel Cristina Rockenbach,Rafael Roesler,Ivan Izquierdo,Esper A. Cavalheiro,Vilma R. Martins,Ricardo R. Brentani +7 more
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TLDR
Electrophysiologic and histologic alterations found in these mice suggest a possible role for PrPc in seizure threshold and/or epilepsy.Abstract:
Summary: Purpose: The physiologic role of the cellular prion protein (PrPc) is unknown. Mice devoid of PrPc develop normally and show only minor deficits. However, electrophysiologic and histologic alterations found in these mice suggest a possible role for PrPc in seizure threshold and/or epilepsy.
Methods: We tested the sensitivity of PrPc knockout mice to seizures induced by single convulsant or repeated subconvulsant (kindling) doses of pentylenetetrazol (PTZ), and to status epilepticus (SE) induced by kainic acid or pilocarpine.
Results: In PTZ kindling, seizure severity progressed faster in the PrPc knockout group, in which 92.8% reached stage 5 or death after 4 days of stimulation, as opposed to 38.4% in wild-type animals. After 10 injections, mortality was 85.7% among knockouts and 15.3% among controls. After a single PTZ injection (60 mg/kg), overall mortality due to seizures was 91% in knockout mice, but only 33% among wild-type animals. Pilocarpine-induced SE (320 mg/kg) caused an 86.7% mortality in knockouts, as opposed to 40% in wild-type animals. Finally, after kainic acid injections (10 mg/kg), 70% of the knockouts developed at least one severe seizure, and 50% showed repetitive seizures, whereas no wild-type animal exhibited observable seizures.
Conclusions: Animals lacking cellular prion protein expression are more susceptible to seizures induced by various convulsant agents. This is perhaps the most striking alteration yet found in PrPc-null mice, who at first analysis appeared to be completely normal. A possible role for PrPc in chronic and idiopathic (familial), secondary, or cryptogenic epilepsies in humans remains to be investigated.read more
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Journal ArticleDOI
Physiology of the Prion Protein
Rafael Linden,Vilma R. Martins,Marco A. M. Prado,Martín Cammarota,Ivan Izquierdo,Ricardo R. Brentani +5 more
TL;DR: A unified view of functional properties of PrP(C) indicates that the prion protein is a dynamic cell surface platform for the assembly of signaling modules, based on which selective interactions with many ligands and transmembrane signaling pathways translate into wide-range consequences upon both physiology and behavior.
Journal ArticleDOI
Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection
Silvio M. Zanata,Marilene H. Lopes,Adriana F. Mercadante,Glaucia N. M. Hajj,Luciana B. Chiarini,Regina Nomizo,Adriana Freitas,A. L. B. Cabral,Kil Sun Lee,Maria A. Juliano,Elizabeth de Oliveira,Saul G. Jachieri,Alma L. Burlingame,Lan Huang,Rafael Linden,Ricardo R. Brentani,Vilma R. Martins +16 more
TL;DR: Cell surface binding and pull‐down experiments showed that recombinant PrPc binds to cellular STI1, and co‐immunoprecipitation assays strongly suggest that both proteins are associated in vivo.
Journal ArticleDOI
The two faces of protein misfolding: gain‐ and loss‐of‐function in neurodegenerative diseases
TL;DR: How two faces of protein misfolding contribute to the pathomechanisms of Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease and prion diseases are summarized.
Journal ArticleDOI
Cellular prion protein transduces neuroprotective signals
Luciana B. Chiarini,Adriana Freitas,Silvio M. Zanata,Ricardo R. Brentani,Vilma R. Martins,Rafael Linden +5 more
TL;DR: Engagement of PrPc transduces neuroprotective signals through a cAMP/PKA‐dependent pathway and may function as a trophic receptor, the activation of which leads to a neuroprot protective state.
Journal ArticleDOI
Biological inorganic and bioinorganic chemistry of neurodegeneration based on prion and Alzheimer diseases.
David R. Brown,Henryk Kozlowski +1 more
TL;DR: A change of the prion protein conformation results in a class of neurodegenerative diseases called the transmissible spongiform encephalopathies (like mad cow and Creutzfeld-Jakob diseases).
References
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Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein
Hansruedi Büeler,Marek Fischer,Yolande Lang,Yolande Lang,Horst Bluethmann,Horst Bluethmann,Hans-Peter Lipp,Stephen J. DeArmond,Stephen J. DeArmond,Stanley B. Prusiner,Stanley B. Prusiner,Michel Aguet,Charles Weissmann +12 more
TL;DR: It is now feasible to determine whether mice devoid of PrPc can propagate prions and are susceptible to scrapie pathogenesis.
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TL;DR: It was found that stimulation of more than one area increases the rate of seizure development, whereas disrupting inter-limbic connections retards seizure development.
Journal ArticleDOI
Prion protein is necessary for normal synaptic function
John Collinge,Miles A. Whittington,Katie C. L. Sidle,Corinne J. Smith,Mark S. Palmer,Anthony R. Clarke,John G. R. Jefferys +6 more
TL;DR: It is argued that loss of function of PrPc may contribute to the early synaptic loss3 and neuronal degeneration seen in Creutzfeldt–Jakob disease and scrapie and bovine spongiform encephalopathy in animals.