Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease.

Machado-Joseph disease is the most frequently found dominantly-inherited cerebellar ataxia. Over-repetition of a CAG trinucleotide in the MJD1 gene translates into a polyglutamine tract within the ataxin 3 protein, which upon proteolysis may trigger Machado-Joseph disease. We investigated the role of calpains in the generation of toxic ataxin 3 fragments and pathogenesis of Machado-Joseph disease. For this purpose, we inhibited calpain activity in mouse models of Machado-Joseph disease by overexpressing the endogenous calpain-inhibitor calpastatin. Calpain blockage reduced the size and number of mutant ataxin 3 inclusions, neuronal dysfunction and neurodegeneration. By reducing fragmentation of ataxin 3, calpastatin overexpression modified the subcellular localization of mutant ataxin 3 restraining the protein in the cytoplasm, reducing aggregation and nuclear toxicity and overcoming calpastatin depletion observed upon mutant ataxin 3 expression. Our findings are the first in vivo proof that mutant ataxin 3 proteolysis by calpains mediates its translocation to the nucleus, aggregation and toxicity and that inhibition of calpains may provide an effective therapy for Machado-Joseph disease.

[Illustrations de Architectura privata] / Matthias Rembold, grav. ; Joseph Furttenbach, aut. du texte

Comprend : [pl.2 double après p.6 : cinq modèles de fenêtres. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.3 double après p.6 : six modèles de fenêtres. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.4 double après p.6 : six modèles de fenêtres. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.5 double dépl. après p.6 : trois modèles de portes ou portails. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.6 double dépl. après p.6 : plan d'une maison. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.7 double dépl. après p.10 : plan d'une maison. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.8 double dépl. après p.14 : plan d'une maison. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.9 double dépl. après p.16 : plan d'une maison. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.910double dépl. après p.18 : plan d'un monastère? Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.11 double dépl. après p.60 : coupe d'une fontaine-grotte rocaille. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.12 double dépl. après p.64 : dessin de la voûte d'une fontaine-grotte rocaille. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.13 double dépl. après p.68 : coupe et plan d'une fontaine-grotte rocaille avec vue du sytème hydraulique. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209] ; [pl.14 double dépl. après p.74 : plans du système hydraulique alimentant une fontaine. Principes d'architecture.] [Cote : V 4282/Microfilm R 122 209]

Catalogue d'une collection de tableaux peints par M. J. [Joseph] Beaume...

[Vente. Art. 1860-03-20. Paris]

The cave (La caverna -1952-1969) by Josep Palau i Fabre: theatre versus philosophical allegory in order both to perform and stop the tragic and dark end of the bright art of thinking

What is the use of representing in performance the image of the cave from book VII of Plato’s Republic? Josep Palau i Fabre considers that in Plato’s dialogues the speakers are mere instruments at the service of his dialectical purpose. The aim of this article is to show how, by turning the myth into a tragedy and relying on Heraclitus’s conflict or war of opposites, the playwright succeeds in favouring a sort of thought which is not one-sided or univocal. On the contrary, in Palau i Fabre’s La Caverna, the tragic hero, the released prisoner transformed by the light of Reality and finally killed by his “cavemates” –after having been imprisoned again and having tried to rescue them from their ignorance or shadows– still leaves them his powerful experience of the agonistikós thought, which might bear fruit in their life to come.