Structural Properties of Polyglutamine Aggregates Investigated via Molecular Dynamics Simulations

Polyglutamine (polyQ) beta-stranded aggregates constitute the hallmark of Huntington disease. The disease is fully penetrant when Q residues are more than 36-40 ("disease threshold"). Here, based on a molecular dynamics study on polyQ helical structures of different shapes and oligomeric states, we suggest that the stability of the aggregates increases with the number of monomers, while it is rather insensitive to the number of Qs in each monomer. However, the stability of the single monomer does depend on the number of side-chain intramolecular H-bonds, and therefore oil the number of Qs. If such number is lower than that of the disease threshold, the beta-stranded monomers are unstable and hence may aggregate with lower probability, consistently with experimental findings. Our results provide a possible interpretation of the apparent polyQ length dependent-toxicity, and they do not support the so-called "structural threshold hypothesis", which supposes a transition from random coil to a beta-sheet structure only above the disease threshold

Transglutaminase activation in neurodegenerative diseases

The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease exhibit increased transglutaminase activity and rises in intracellular calcium concentrations, which may be related. The aberrant activation of transglutaminase by calcium is thought to give rise to a variety of pathological moieties in these diseases, and the inhibition has been shown to have therapeutic benefit in animal and cellular models of neurodegeneration. Given the potential clinical relevance of transglutaminase inhibitors, we have also reviewed the recent development of such compounds

Arabidopsis thaliana Atrab28: a nuclear targeted protein related to germination and toxic cation tolerance

The Arabidopsis gene Atrab28 has been shown to be expressed during late embryogenesis. The pattern of expression of Atrab28 mRNA and protein during embryo development is largely restricted to provascular tissues of mature embryos, and in contrast to the maize Rab28 homologue it cannot be induced by ABA and dehydration in vegetative tissues. Here, we have studied the subcellular location of Atrab28 protein and the effect of its over-expression in transgenic Arabidopsis plants. The Atrab28 protein was mainly detected in the nucleus and nucleolus of cells from mature embryos. In frame fusion of Atrab28 to the reporter green fluorescent protein (GFP) directed the GFP to the nucleus in transgenic Arabidopsis and in transiently transformed onion cells. Analysis of chimeric constructs identified an N-terminal region of 60 amino acids containing a five amino acid motif QPKRP that was necessary for targeting GFP to the nucleus. These results indicate that Atrab28 protein is targeted to the nuclear compartments by a new nuclear localization signal (NLS). Transgenic Arabidopsis plants, with gain of Atrab28 function, showed faster germination rates under either standard or salt and osmotic stress conditions. Moreover, improved cation toxicity tolerance was also observed not only during germination but also in seedlings. These results suggest a role of Atrab28 in the ion cell balance during late embryogenesis and germination.This work has been supported by grant BIO 2000-1562 from Plan Nacional de Investigación Científica y Desarrollo Tecnológico.Peer reviewe

Expression and cellular localization of Atrab28 during Arabidopsis embryogenesis

The maize abscisic acid (ABA)-responsive gene rab28 has been shown to be ABA-inducible in embryos and vegetative tissues, expression being mostly restricted to vascular elements during late embryogenesis. In the course of an expressed sequence tags (ESTs) programme, we have isolated an Arabidopsis thaliana gene, Atrab28, encoding the orthologue of maize rab28. The Atrab28 cDNA is 1090 bp long, including a poly(A)+ stretch, and encodes a polypeptide of 262 amino acids. Atrab28 antibody against the recombinant protein recognizes a polipeptide of about 30 kDa and pI 6, in close agreement with the predicted molecular mass and pI. As for maize rab28, expression studies with Atrab28 revealed high specificity for embryo tissues, transcription being stimulated by the transcriptional activator abi3. In contrast, Atrab28 was not induced in vegetative tissues by ABA, osmotic stress or dehydration. The expression of Atrab28 mRNA and the accumulation of Atrab28 protein was largely restricted to provascular tissues of mature embryos and in the seed coat outer tegument and embryo and silique epidermis, as revealed by in situ hybridization and immunocytochemistry with anti-Atrab28 antibodies.This work was supported by a joint programme between the CNRS (Centre National de la Recherche Scientifique) and the CSIC (Consejo Superior de Investigaciones Científicas), the European Associated Laboratory between Perpignan and Barcelona in Plant Molecular and Cellular Biology. In addition, both Perpignan and Barcelona groups are members of the European project ‘Characterising and engineering abscisic acid action’ (Biotech BIO4-CT96-0062). Work in Barcelona was supported in part by the European Communities Biotech Programme, as part of the Project of Technological Priority and by grant BIO94-0750 from Plan Nacional de Investigatión Científica y Desarrollo Tecnológico. Work in Perpignan was supported by CNRS grants URA 565 and UMR 5545.Peer reviewe

Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase

There is no treatment for the neurodegenerative disorder Huntington disease (HD). Cystamine is a candidate drug; however, the mechanisms by which it operates remain unclear. We show here that cystamine increases levels of the heat shock DnaJ-containing protein 1b (HSJ1b) that are low in HD patients. HSJ1b inhibits polyQ-huntingtin–induced death of striatal neurons and neuronal dysfunction in Caenorhabditis elegans. This neuroprotective effect involves stimulation of the secretory pathway through formation of clathrin-coated vesicles containing brain-derived neurotrophic factor (BDNF). Cystamine increases BDNF secretion from the Golgi region that is blocked by reducing HSJ1b levels or by overexpressing transglutaminase. We demonstrate that cysteamine, the FDA-approved reduced form of cystamine, is neuroprotective in HD mice by increasing BDNF levels in brain. Finally, cysteamine increases serum levels of BDNF in mouse and primate models of HD. Therefore, cysteamine is a potential treatment for HD, and serum BDNF levels can be used as a biomarker for drug efficacy

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

http://www.sciencedirect.com/science/article/B6SYS-4V59VTB-1/2/2a1ab641b7c1e5d4b9ca6f8c2134bdc