Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS

A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS

Characterization of a lysine-specific histone demethylase from Arabidopsis thaliana RID A-4573-2009

Arabidopsis thaliana has four genes with close homology to human histone H3 lysine 4 demethylase (HsLSD1), a component of various transcriptional corepressor complexes that often also contain histone deacetylases and the corepressor protein CoREST. All four Arabidopsis proteins contain a flavin amine oxidase domain and a SWIRM domain, the latter being present in a number of proteins involved in chromatin regulation. Here, we describe the heterologous expression and biochemical characterization of one of these Arabidopsis proteins (AtLSD1) and show that, similarly to HsLSD1, it has demethylase activity toward mono- and dimethylated Lys4 but not dimethylated Lys9 and Lys27 of histone 3. Modeling of the AtLSD1 three-dimensional structure using the HsLSD1 crystal structure as a template revealed a high degree of conservation of the residues building up the active site and some important differences. Among these differences, the most prominent is the lack of the HsLSD1 Tower domain, which has been shown to interact with CoREST and to be indispensable for HsLSD1 demethylase activity. This observation, together with AtLSD1 peculiar surface electrostatic potential distribution, suggests that the molecular partners of AtLSD1 are probably different from those of the human orthologue

Characterization of a Lysine-Specific Histone Demethylase from Arabidopsis thaliana.

Arabidopsis thaliana has four genes with close homology to human histone H3 lysine 4 demethylase (HsLSD1), a component of various transcriptional corepressor complexes that often also contain histone deacetylases and the corepressor protein CoREST. All four Arabidopsis proteins contain a flavin amine oxidase domain and a SWIRM domain, the latter being present in a number of proteins involved in chromatin regulation. Here, we describe the heterologous expression and biochemical characterization of one of these Arabidopsis proteins (AtLSD1) and show that, similarly to HsLSD1, it has demethylase activity toward mono- and dimethylated Lys4 but not dimethylated Lys9 and Lys27 of histone 3. Modeling of the AtLSD1 three-dimensional structure using the HsLSD1 crystal structure as a template revealed a high degree of conservation of the residues building up the active site and some important differences. Among these differences, the most prominent is the lack of the HsLSD1 Tower domain, which has been shown to interact with CoREST and to be indispensable for HsLSD1 demethylase activity. This observation, together with AtLSD1 peculiar surface electrostatic potential distribution, suggests that the molecular partners of AtLSD1 are probably different from those of the human orthologue

A new peptide from Crotalus atrox snake venom

The presence of new hypotensive peptides, possibly not related to ACE inhibition, has been investigated on 66 snake venoms from crotalid, viperid and elapid families. Only the venom of Crotalus atrox showed a substantial amount of a new decapeptide, called POL-236, with the following aminoacid sequence: PYR-LEU-TRP-PRO-ARG-PRO-GLN-ILE-PRO-PRO. Pharmacological assays performed on the synthesized peptide revealed effects on blood pressure, probably derived from vascular and cardiac interferences

The complete amino acid sequence of human Cu/Zn superoxide dismutase.

[No abstract available

The primary structure of human liver manganese superoxide dismutase

The complete amino acid sequence of manganese superoxide dismutase from human liver was determined. The sequence was deduced following characterization of the peptides obtained from tryptic, chymotryptic, and Staphylococcus aureus digests of the apoprotein. Chemical cleavage with dimethyl sulfoxide-hydrobromic acid was also carried out. The amino acid sequence listed below is made up of 196 amino acids and the two subunit polypeptides in the native enzyme appear to be identical. No homology was observed with copper/zinc containing class of superoxide dismutase